Substituted diketopiperazines as oxytocin antagonists

ABSTRACT

A method of treating or preventing diseases or conditions mediated through the action of oxytocin which comprises administering to a human in need thereof of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

This application is a continuation of U.S. application Ser. No.10/499,177, filed Jan. 31, 2005, now U.S. Pat. No. 7,514,437, which is a371 of International Application PCT/EP02/14823 filed Dec. 20, 2002,which claims priority to GB Application 0130677.8 filed Dec. 21, 2001.

This invention relates to the use of a class of diketopiperazinederivatives as potent and selective antagonists of oxytocin, to novelcompounds within that class and to processes for their preparation.

U.S. Pat. No. 5,817,751 describes combinatorial and solid phase methodsfor the synthesis of diverse diketopiperazine derivatives and the use ofthese methods to create libraries of diverse diketopiperazinederivatives.

WO99/47549 describes diketopiperazine derivatives including 3-benzyl-2,5diketopiperazine derivatives as inhibitors of fructose 1,6-bisphospate(FBPase). WO99/38844 describes a method for preparing N-[aliphatic oraromatic) carbonyl]-2-aminoacetamide compounds and their cyclisation togive inter alia diketopiperazine derivatives.

WO99/37304 describes oxaheterocyclyl compounds including oxapiperazinylcompounds that are inhibitors of Factor Xa.

The hormone oxytocin is potent contractor of the uterus and is used forthe induction or augmentation of labour. Also the density of uterineoxytocin receptors increases significantly by >100 fold during pregnancyand peaks in labour (pre-term and term). Pre-term births/labour (between24 and 37 weeks) causes about 60% of infant mortality/morbidity and thusa compound which inhibits the uterine actions of oxytocin e.g. oxytocinantagonists, should be useful for the prevention or control of pre-termlabour.

We have found a class of diketopiperazine derivatives which exhibit aparticularly useful level of activity as selective antagonists at theoxytocin receptor.

The present invention thus a method of treating or preventing diseasesor conditions mediated through the action of oxytocin which comprisesadministering to a mammal in need thereof of an effective amount of acompound of the formula (I)

and/or a physiologically acceptable derivative thereof, wherein:R₁ represents aryl (C₁₋₄) alkyl or a 5-7 membered cycloalkyl groupoptionally substituted with one or more hydroxyl groups which is fusedto an optionally substituted benzene ring;R₂ represents C₁₋₆alkyl (optionally substituted by a C₁₋₂alkoxy,C₁₋₂alkylthio, di(C₁₋₂alkyl) amino or a C₃₋₆ cycloalkyl group) orC₃₋₆cycloalkyl, or 5-6 membered heterocyclic group containing a singlehetero atom selected from O, S or N, which nitrogen atom carries ahydrogen atom or a methyl or ethyl group;R₃ represents optionally substituted phenyl, a 5 or 6 membered heteroaryl group or a fused bicyclic ring system containing 9-10 ring memberswhich may be a carbocyclic group or it may contain up to 3 heteroatomsselected from O, S or N and one of the fused rings is benzene;R₄ represents OH or OC₁₋₄ alkyl (optionally substituted withC₁₋₄alkylcarbonyloxy) or NR₅R₆;R₅ represents hydrogen, C₁₋₆alkyl (optionally substituted withC₁₋₄alkoxy) or C₃₋₇cycloalkyl;R₆ represents hydrogen, C₁₋₄alkoxy, C₃₋₇cycloalkyl, C₁₋₄alkyl[optionally substituted with one or more groups selected from, carboxyl,C₁₋₄alkylsulphonyl, or C₁₋₄alkoxycarbonyl], C₂₋₄alkyl [optionallysubstituted with one or more groups selected from halogen, hydroxy,C₁₋₄alkoxy or NR₇R₈ wherein R₇ and R₅ independently represent hydrogenor C₁₋₄alkyl or together with the nitrogen atom to which they areattached to form a 3-7 membered saturated heterocyclic ring which maycontain an additional heteroatom selected from O, S or N (and whichheterocyclic group may be substituted by 1 to 3 groups selected fromC₁₋₃alkyl, hydroxy, C₁₋₃ alkoxy (optionally substituted by C₃₋₆cycloalkyl or optionally substituted phenyl), C₃₋₆cycloalkyl orNR_(c)R_(d) wherein R_(c) and R_(d) each independently represent a groupselected from C₁₋₃alkyl (optionally substituted by C₃₋₆ cycloalkyl oroptionally substituted phenyl) or C₃₋₆ cycloalkyl)] or R₆ represents aphenyl or benzyl group (optionally substituted by one or more methoxy orbenzyloxy groups) or an optionally substituted heteroarylmethyl group ora heteroaryl group or C₃₋₇ cycloalkyl or the group CH₂CONR₉R₁₀ whereinR₉ represents hydrogen or C₁₋₄alkyl, R₁₀ represents hydrogen, C₁₋₄alkyloptionally substituted by a 5 or 6 membered heteroaryl group or R₉, R₁₀and the nitrogen atom to which they are attached together form a 5 or 6membered saturated heterocyclic ring and wherein the 6 memberedheterocyclic group may contain an additional heteroatom selected fromoxygen, sulphur or nitrogen and the additional nitrogen atom eithercarries a hydrogen atom or a C₁₋₄alkyl or C₁₋₄alkanoyl group; or R₅ andR₆ together with the nitrogen atom to which they are attached form a 3to 7 membered saturated heterocyclic ring which heterocycle may containan additional heteroatom selected from oxygen, sulphur and nitrogen andwherein the sulphur atom may be in an oxidised form e.g. SO₂ and theadditional nitrogen atom either carries a hydrogen atom or a C₁₋₄alkylor a C₁₋₄alkanoyl group or a C₁₋₄alkylsulphonyl group or a C₁₋₃alkoxyC₂₋₄ alkyl [and which heterocyclic groups may be substituted byone or more halogen atoms or a group selected from C₁₋₃alkyl, hydroxy,oxo, C₃₋₆cycloalkyl or NR_(e)R_(f) wherein R_(e) and R_(f) eachindependently represent a group selected from C₁₋₃alkyl (optionallysubstituted by C₃₋₆ cycloalkyl or optionally substituted phenyl) or C₃₋₆cycloalkyl].

The invention also provides novel compounds of formula (I). Aparticularly useful class of novel compounds of formula (I) are thosewherein R₁ is 2-indanyl optionally substituted by hydroxyl and moreparticularly a 2-indanyl group and R₂, R₃ and R₄ have the meaningsdefined above and/or physiologically acceptable derivatives thereof. Afurther useful class of novel compounds of formula (I) are those whereinR₁ is a 2-phenethyl and R₂, R₃ and R₄ have the meanings defined aboveand/or physiologically acceptable derivatives thereof.

The compounds of formula (I) contain at least three centers ofasymmetry, namely the carbon atoms carrying the substituents R₁, R₂ andR₃ respectively and it is to be understood that formula (I) includes allpossible stereoisomers and mixtures thereof. The substituent R₃ mayexist in more than one tautomeric form and it is to be all understoodthat formula (I) includes all possible tautomeric forms and mixturesthereof.

The compounds of formula (I) wherein at least one of the groups R₁, R₂,R₃ or R₄ contains a basic or acidic grouping may form salts withphysiologically acceptable acids or bases and reference to compounds offormula (I) herein includes such salts.

As used herein, the terms “physiologically acceptable derivative” or“pharmaceutically acceptable derivative”, mean any pharmaceuticallyacceptable salt, solvate, or prodrug e.g. ester or carbamate, or salt orsolvate of such a prodrug, of a compound of formula (I), which uponadministration to the recipient is capable of providing (directly orindirectly) a compound of formula (I), or an active metabolite orresidue thereof. Preferred pharmaceutically acceptable derivatives aresalts and solvates.

As used herein, the term “prodrug” means a compound which is convertedwithin the body, e.g. by hydrolysis in the blood, into its active formthat has medical effects. Pharmaceutically acceptable prodrugs aredescribed in T. Higuchi and V. Stella, Prodrugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche,ed., Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference. Esters may be active in their own right and/or behydrolysable under in vivo conditions in the human body. Suitablepharmaceutically acceptable in vivo hydrolysable ester groups includethose which break down readily in the human body to leave the parentacid or its salt. Examples of such esters include alkyl and1-(acetyloxy)ethyl esters.

The term alkyl as a group or part of a group refers to a straight orbranched alkyl group e.g. methyl, ethyl, propyl, isopropyl, n-butyl,1-methylpropyl, 2-methylpropyl, t-butyl, pentyl or hexyl.

The term C₃₋₆ cycloalkyl as a group or part of a group includescyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. The termC₃₋₇cycloalkyl also includes cycloheptyl.

The term halogen refers to fluorine, chlorine, bromine or iodine.

Unless otherwise specified the term optionally substituted phenyl refersto a phenyl group which may be substituted by 1 to 3 substituents whichmay be the same or different and selected from halogen, hydroxy,C₁₋₄alkyl (optionally substituted by 1-3 halogen atoms or NR_(g)R_(h)[wherein R_(g) is hydrogen or C₁₋₄ alkyl, R_(h) is hydrogen, C₁₋₄ alkyl,or R_(g) and R_(h) together with the nitrogen atom to which they areattached to form a 5 to 7 membered ring, which ring is saturated and maycontain an additional heteroatom selected from nitrogen, oxygen orsulphur]), C₁₋₄ alkylsulphonyl, carboxyl, C₁₋₄ alkoxycarbonyl,di(C₁₋₄alkyl)aminocarbonyloxy, C₁₋₄alkoxy (optionally substituted by 1-3halogen atoms, amino, C₁₋₄ alkylamino or di-(C₁₋₄alkyl)amino), phenyl(optionally substituted by halogen or alkylaminosulphonyl), C₁₋₄alkoxy,NR_(a)R_(b) [wherein R_(a) is hydrogen or C₁₋₄ alkyl, R_(b) is hydrogen,C₁₋₄ alkyl, C₁₋₄ alkanoyl or C₁₋₄ alkylsulphonyl or R_(a) and R_(b)together with the nitrogen atom to which they are attached to form a 5to 7 membered ring, which ring is saturated and may be substituted byhydroxyl or 1 or 2 C₁₋₄alkyl groups or may be spiro-fused to a dioxalanering or may contain an additional heteroatom selected from nitrogen,oxygen or sulphur and may be substituted by 1 or 2 C₁₋₄alkyl groups, orwhich ring is unsaturated and contains 1-3 additional nitrogen atoms], a5 or 6 membered heteroaryl group, an optionally N-substitutedaminocarbonyl or aminosulphonyl group (wherein the substituents may be 1or 2 C₁₋₄ alkyl groups) or a dihydroxyboryl group).

The term 5 membered heteroaryl refers to a 5 membered ring whichcontains a heteroatom selected from oxygen, sulphur or nitrogen andwhich may also contain from 1 to 3 additional nitrogen atoms and whichgroups may be substituted by 1 or more groups selected from halogen,trifluoromethyl, C₁₋₄ alkyl, cycloalkyl, heteroaryl, saturatedheterocyclic, or phenyl groups. Examples of such 5 membered heteroarylgroups include furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolylor tetrazolyl and these heterocycles may be substituted as describedabove.

The term 6-membered heteroaryl group refers to a 6-membered unsaturatedring which contains from 1 to 3 nitrogen atoms and which may besubstituted by 1 to 3 C₁₋₄ alkyl groups, or trifluoromethyl, or alkoxygroups. Examples of such groups include pyridyl, methylpyridyl,trifluoromethylpyridyl, pyrimidinyl and triazinyl.

When R₃ is a 5 or 6 membered heteroaryl group this is linked to the restof the molecule via a carbon atom in the ring.

When R₃ is a fused bicyclic carbocyclic ring system this may be forexample a naphthyl, tetrahydronaphthyl, indanyl or indenyl group.

When R₃ is a fused bicyclic system containing up to 3 heteroatoms whichmay be the same or different, this is conveniently a 6, 5 or 6,6 ringsystem wherein the heterocycle may be partially saturated or togetherwith the benzene ring to which it is fused to form a heteroaryl groupand the heterocycle may be substituted by 1 or 2 groups selected fromC₁₋₄ alkyl or halogen or haloalkyl and or may contain a carbonyl group.The said R₃ group may be linked to the rest of the molecule via a carbonatom in the benzene ring or a carbon atom in the heterocyclic group.

When R₃ is a fused 6,6 heteroaryl group the hetero ring contains from 1to 3 nitrogen atoms and examples of such heteroaryl groups includequinolinyl, isoquinolinyl, phthalazinyl, cinnolinyl, quinazolinyl,quinoxalinyl, 1,2,3 benzotriazinyl or 1,2,4 benzotriazinyl.

When R₃ is a 6,5 bicyclic heteroaryl group the 5 membered heterocyclecontains a hetero atom selected from O, S or N and may in addition alsocontain a further 1 or 2 nitrogen atoms and the heterocyclic ring mayalso be substituted by 1 or 2 C₁₋₄ alkyl or halogen or haloalkyl and ormay contain a carbonyl group. Examples of such 6,5 bicyclic heteroarylgroups include benzofuranyl, benzothienyl, indolyl, benzo-oxadiazolyl,benzothiadiazolyl, benzo-oxazolyl, benzothiazolyl, benzoisothiazolyl,benzoisoxazolyl, benzimidazolyl, indazolyl or benzotriazolyl and thesegroups may be substituted as described above.

When R₃ is a 6,6 or 6,5 bicyclic heterocyclic group and the heterocycleis partially saturated, this may contain 1 or 2 heteroatoms selectedfrom O, S or N. Examples of such groups include indolinyl, isoindolinyl,dihydrobenzofuranyl, dihydrobenzothienyl, 1,3-benzodioxolyl,benzopyrrolyl, 1,3-benzodithiolyl 1,4-benzodioxanyl, phthalyl,thiophthalyl, chromanyl or chromenyl and the groups may be substitutedby one or more halogen or C₁₋₄ alkyl groups, haloalkyl, or may contain acarbonyl group.

When R₃ is a fused bicyclic heteroaryl linked via the benzene ringtherein then suitable examples of such a group include 6-quinolinyl,4-isoindolinyl, 4-(N-methyl-isoindolinyl, benzimidazolyl,benzothiazolyl, benzofuranyl, benzothienyl, benzimidazolyl benzoxazolyl,2 methyl-benzo-oxazolyl, benzothiadiazolyl, benzotriazolyl and 1-methylbenzotriazolyl.

When R₃ is a fused bicyclic heteroaryl group linked via the heteroarylring this may be for example a 2-benzofuranyl, 2-benzothienyl or2-N-methylindolyl group.

When R₃ is a 6,6 or 6,5 heterocyclic group wherein the heterocycle ispartially saturated this is conveniently linked via the benzene ringtherein and suitable examples include dihydrobenzofuran,dihydrobenzopyrrole, 1,3-benzodioxolyl, 2,2-difluoro-1,3-benzodioxolyl,and 1,4-benzodioxanyl.

When R₃ is a substituted phenyl group the said group convenientlycarries from 1 to 3 substituents which may be the same or differentselected from fluorine, chlorine, bromine C₁₋₃alkyl(methyl),C₁₋₃haloalkyl (trifluoromethyl), C₁₋₃alkoxy (methoxy, ethoxy),haloalkoxy (trifluoromethoxy), aminoethoxy e.g. dimethylaminoethoxy,C₁₋₃alkoxycarbonyl, carboxy, hydroxy, phenyl or phenyl (substituted byhalogen or alkylaminosulphonyl), NR_(a)R_(b) [wherein R_(a) is hydrogenor C₁₋₂alkyl and R_(b) is C₁₋₂alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulphonyl,C₁₋₃alkylaminocarbonyl] or NR_(a)R_(b) represents a pyrrolidino orpiperidino ring, which ring may be substituted by a C₁₋₂alkyl, hydroxylor a 2,2-1,3-dioxolane group or NR_(a)R_(b) represents a morpholino or apiperazino group which groups may be substituted by 1 or 2 C₁₋₂alkylgroups or NR_(a)R_(b) represents a 5 or 6 membered heteroaryl groupcontaining from 1 to 4 nitrogen atoms (such as a 1-imidazolyl,1,2-pyrazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl substitutent),C₁₋₃alkylsulphonyl, C₁₋₃alkylaminocarbonyl, C₁₋₃alkylaminosulphonyl,dihydroxyboryl or a 5 or 6 membered atom heteroaryl group containingfrom 1 to 4 nitrogen atoms and which is linked to the phenyl group via acarbon atom in the heteroaryl group (for example pyridyl, pyrazolyl,imidazolyl or tetrazol 5-yl, which heteroaryl groups may be substitutedby 1 or more C₁₋₄ alkyl groups.

Examples of suitable R₃ groups wherein R₃ is optionally substitutedphenyl include phenyl, halophenyl such as 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl,2-chlorophenyl, 4-bromophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl,2,4-difluorophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl,2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2fluoro-4-bromophenyl, 4-chloro-3-fluorophenyl 2,3,4-trifluorophenyl2,4,5-trifluorophenyl or 2,4,6-trifluorophenyl,2-fluoro-4,5-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl,4-fluoro-3-methoxyphenyl, 2-fluoro-4 methoxyphenyl, 2-fluoro-4hydroxyphenyl, 2-fluoro-4-dimethylaminomethylphenyl,2-fluoro-4-hydroxymethylphenyl, 3-fluoro-4-(4-morpholino)phenyl,3-fluoro-4-carboxymethyloxyphenyl,3-fluoro-4-t-butyloxycarbonylmethyloxyphenyl,3-fluoro-4-dimethylaminocarbonyloxyphenyl, 3-chloro-4trifluoromethoxyphenyl, 2,3-difluoro-4-methyl-phenyl,4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl,4-methoxyphenyl, 4-methoxycarbonylphenyl, 3-methoxycarbonyphenyl,4-methylsulphonylphenyl, 4-methylaminocarbonylphenyl,4-aminocarbonylphenyl, 4-methylaminosulphonylphenyl,3-(3-pyrazyolyl)phenyl, 4-(3-pyrazolyl)phenyl, 4-(4-pyrazolyl)phenyl,4-(3-pyridyl)phenyl, 4-(2-pyridylphenyl), 4-(2-imidazolyl)phenyl,3-(2-imidazolyl)phenyl, 4-(1-t-butyl-tetrazol-5-yl)phenyl,4-methylaminophenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl,4-acetylaminophenyl, 3-acetylaminophenyl, 4-hydroxy-3-acetylaminophenyl,4-methylsulphonylaminophenyl, 4-N-methylpiperazinophenyl,4-N-pyrrolidinophenyl, 2-fluoro-4-(4-morpholino)phenyl,4-(4-morpholino)phenyl, 4-(4-hydroxypiperidino)phenyl,2-fluoro-4-(4-hydroxypiperidino)phenyl, 3-(1-pyrazolyl)phenyl,4-(1-pyrazolyl)phenyl, 4-(1-3,5 di-t-butylpyrazolyl)phenyl,3-(1-imidazolyl)phenyl, 4-(1-imidazolyl)phenyl,4-(1-1,2,4-triazolyl)phenyl, 4-(1-1,2,3-triazolyl)phenyl,4-(2-4,-t-butylthiazolyl)phenyl, 4-(5-2-t-butyltetrazolyl)phenyl, 4-(4spiro-1,3-dioxolanyl)piperidinophenyl, 4-(4-fluorophenyl)phenyl,4-(4-ethylaminosulphonylphenyl)phenyl, 4-dimethylaminoethoxyphenyl or3-(dihydroxyboryl)phenyl.

When R₃ is a 5 or 6 membered heteroaryl group suitable examples of suchgroups include 2-furanyl, 3-thienyl, 3-furanyl, 2-thienyl,4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chloro-2-thienyl,3-fluoro-5-methyl-2-thienyl, 5-fluoro-2-thienyl, 5-methyl-2-thienyl,5-methyl-2-furanyl, 5-bromo-2-furanyl, 4,5-dimethyl-2-furanyl,2,3-dimethyl-5-thienyl, 5-trifluoromethyl-2-furanyl,2-furanyl-4-carboxylic acid methylamide, 2-furanyl-5-carboxylic acidmethylamide, 2-pyridyl, 6-methyl-2-pyridyl, 6-methyl-3-pyridyl,6-hydroxy-3-pyridyl, 6-methoxy-3-pyridyl, 6-trifluoromethyl-3-pyridyl,3-pyridyl, 4-pyridyl, 3,5-pyrimidinyl, 2-thiazolyl, 4-oxazolyl,4-thiazolyl, 2-methyl-4-oxazolyl, 2-ethyl-4-oxazolyl,2-cyclopropyl-4-oxazolyl, 2-trifluoromethyl-4-oxazolyl,2,5-dimethyl-4-oxazolyl, 4-thiazolyl, 2-methyl-4-thiazolyl,2-trifluoromethyl-4-thiazolyl, 2-trifluoromethyl-5-thiazolyl,4-isoxazolyl, 1-methyl-4-pyrazolyl, 1,3-dimethyl-5-pyrazolyl,5-(2-pyridyl)-2-thienyl, 2-(4-morpholino)-5-thiazolyl or2-(4-methyl-1-piperazino)-5-thiazolyl.

When R₃ is an optionally substituted fused bicyclic ring system examplesof suitable groups include 2,3-dihydro-1-benzofuran-5-yl,1,3-benzodioxol-5-yl, 1H-1,2,3-benzotriazol-5-yl,2,3-dihydro-1,4-benzodioxin-6-yl, 2,2-difluoro-1,3-benzodioxol-5-yl,1,3-benzothiazol-6-yl, 1-methyl-1H-1,2,3-benzotriazol-5-yl,1-methyl-1H-1,2,3-benzotriazol-6-yl, 1,2,3-benzothiadiazol-6-yl,2-methyl-1,3-benzoxazol-5-yl, 2-methyl-1,3-benzoxazol-6-yl,1-benzofuran-5-yl, 1-methyl-1H-lindol-5-yl, 1-benzothien-5-yl,1-benzofuran-6-yl, 1H-indol-6-yl, 1-methyl-1H-benzimidazol-6-yl,1-methyl-1H-benzimidazol-5-yl, 3-methyl-1,2-benzoisoxazol-5-yl,2-fluoro-1-benzofuran-5-yl, 1H-indol-5-yl, 2-methyl-1H-benzofuran-5-yl,1H-indazol-5-yl, 1H-indazol-6-yl, 1-benzofuran-2-yl or1-methyl-1H-benzimidazol-2-yl.

When the group R₁ is a 5-7 membered cycloalkyl group which is fused toan optionally substituted benzene ring the optional substituents may befrom 1 to 3 groups which may be the same or different and selected fromhalogen, alkyl, alkoxy, hydroxy, trifluoromethyl, nitro, carboxyl,alkoxycarbonyl or carboxamido.

When the group R₁ is aralkyl the aryl moiety is phenyl optionallysubstituted by 1 to 3 groups which may be the same or different andselected from halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, nitro,carboxyl, alkoxycarbonyl or carboxamido.

Examples of suitable R₁ groups include phenethyl or indanyl optionallysubstituted by hydroxyl e.g. 2-indanyl, 1-hydroxy-2-indanyl,5-hydroxy-2-indanyl. Examples of suitable R₂ groups include C₃₋₄alkyle.g. isopropyl, 1-methylpropyl or 2-methylpropyl, C₃₋₆ cycloalkyl e.g.cyclopentyl.

Conveniently R₄ is hydroxy, C₁₋₄ alkoxy e.g. methoxy, propoxy, t-butoxy,1-acetyloxyethoxy or NR₅R₆.

A preferred class of compounds of formula (I) are those wherein R₄represents hydroxy or the group NR₅R₆ or more preferably NR₅R₆.

A further preferred class of compounds is represented by formula (1a)

wherein the groups R₁, R₂, R₃ and R₄ have the meanings defined forformula (I) Conveniently R₁ is a group selected from 2-phenethyl or2-indanyl optionally substituted by hydroxyl and more particularly2-indanyl. Conveniently R₂ is a group selected from isopropyl, 1-methylpropyl, 2-methylpropyl or cyclopentyl and more preferably R₂ is a groupselected from 1-methylpropyl, or 2-methylpropyl.

Conveniently R₃ is a group selected from phenyl, halophenyl such as2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl,3-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 2,3-difluorophenyl,3,4-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl,2,5-difluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 2 fluoro-4-bromophenyl, 4-chloro-3-fluorophenyl2,3,4-trifluorophenyl 2,4,5-trifluorophenyl or 2,4,6-trifluorophenyl,2-fluoro-4,5-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl,4-fluoro-3-methoxyphenyl, 2-fluoro-4 methoxyphenyl, 2-fluoro-4hydroxyphenyl, 2-fluoro-4-dimethylaminomethylphenyl,2-fluoro-4-hydroxymethylphenyl, 3-fluoro-4-(4-morpholino)phenyl,3-fluoro-4-carboxymethyloxyphenyl,3-fluoro-4-t-butyloxycarbonylmethyloxyphenyl,3-fluoro-4-dimethylaminocarbonyloxyphenyl, 3-chloro-4trifluoromethoxyphenyl, 2,3-difluoro-4-methyl-phenyl,4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl,4-methoxyphenyl, 4-methoxycarbonylphenyl, 3-methoxycarbonyphenyl,4-methylsulphonylphenyl, 4-methylaminocarbonylphenyl,4-aminocarbonylphenyl, 4-methylaminosulphonylphenyl,3-(3-pyrazyolyl)phenyl, 4-(3-pyrazolyl)phenyl, 4-(4-pyrazolyl)phenyl,4-(3-pyridyl)phenyl, 4-(2-pyridylphenyl), 4-(2-imidazolyl)phenyl,3-(2-imidazolyl)phenyl, 4-(1-t-butyl-tetrazol-5-yl)phenyl,4-methylaminophenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl,4-acetylaminophenyl, 3-acetylaminophenyl, 4-hydroxy-3-acetylaminophenyl,4-methylsulphonylaminophenyl, 4-N-methylpiperazinophenyl,4-N-pyrrolidinophenyl, 2-fluoro-4-(4-morpholino)phenyl,4-(4-morpholino)phenyl, 4-(4-hydroxypiperidino)phenyl,2-fluoro-4-(4-hydroxypiperidino)phenyl, 3-(1-pyrazolyl)phenyl,4-(1-pyrazolyl)phenyl, 4-(1-3,5 di-t-butylpyrazolyl)phenyl,3-(1-imidazolyl)phenyl, 4-(1-imidazolyl)phenyl,4-(1-1,2,4-triazolyl)phenyl, 4-(1-1,2,3-triazolyl)phenyl,4-(2-4,-t-butylthiazolyl)phenyl, 4-(5-2-t-butyltetrazolyl)phenyl, 4-(4spiro-1,3-dioxolanyl)piperidinophenyl, 4-(4-fluorophenyl)phenyl,4-(4-ethylaminosulphonylphenyl)phenyl, 4-dimethylaminoethoxyphenyl,3-(dihydroxyboryl)phenyl, 2-furanyl, 3-thienyl, 3-furanyl, 2-thienyl,4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chloro-2-thienyl,3-fluoro-5-methyl-2-thienyl, 5-methyl-2-thienyl, 5-methyl-2-furanyl,5-bromo-2-furanyl, 4,5-dimethyl-2-furanyl, 5-trifluoromethyl-2-furanyl,2-furanyl-4-carboxylic acid methylamide, 2-furanyl-5-carboxylic acidmethylamide, 2-pyridyl, 6-methyl-2-pyridyl, 6-methyl-3-pyridyl,6-methoxy-3-pyridyl, 6-hydroxy-3-pyridyl, 6-trifluoromethyl-3-pyridyl,3-pyridyl, 4-pyridyl, 3,5-pyrimidinyl, 2-thiazolyl, 2-methyl-4-oxazolyl,2-ethyl-4-oxazolyl, 2-cyclopropyl-4-oxazolyl,2-trifluoromethyl-4-oxazolyl, 2,5-dimethyl-4-oxazolyl, 4-thiazolyl,2-methyl-4-thiazolyl, 2-trifluoromethyl-4-thiazolyl,2-trifluoromethyl-5-thiazolyl, 1-methyl-4-pyrazolyl,1,3-dimethyl-5-pyrazolyl, 5-(2-pyridyl)-2-thienyl,2,3-dihydro-1-benzofuran-5-yl, 1,3-benzodioxol-5-yl,1H-1,2,3-benzotriazol-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl,2,2-difluoro-1,3-benzodioxol-5-yl, 1,3-benzothiazol-6-yl,1-methyl-1H-1,2,3-benzotriazol-5-yl,1-methyl-1H-1,2,3-benzotriazol-6-yl, 1,2,3-benzothiadiazol-6-yl,2-methyl-1,3-benzoxazol-5-yl, 2-methyl-1,3-benzoxazol-6-yl,1-benzofuran-5-yl, 1-methyl-1H-lindol-5-yl, 1-benzothien-5-yl,1-benzofuran-6-yl, 1H-indol-6-yl, 1-methyl-1H-benzimidazol-6-yl,1-methyl-1H-benzimidazol-5-yl, 3-methyl-1,2-benzoisoxazol-5-yl,2-fluoro-1-benzofuran-5-yl, 1H-indol-5-yl, 2-methyl-1H-benzofuran-5-yl,1H-indazol-5-yl, 1H-indazol-6-yl, 1-benzofuran-2-yl or1-methyl-1H-benzimidazol-2-yl.

Conveniently the group R₅ is hydrogen, C₁₋₄alkyl e.g. methyl orC₁₋₄alkoxyC₂₋₄alkyl e.g. 2-methoxyethyl and R₆ is a group selected fromhydrogen, C₁₋₄alkoxy e.g. methoxy, C₁₋₄alkyl e.g. methyl, n-propyl,isopropyl or t-butyl, C₁₋₄ alkyl substituted by 1 to 3 halogen atomse.g. 2,2,2-trifluoroethyl or 2-fluoroethyl, C₁₋₄alkyl substituted byalkoxycarbonyl or carboxyl e.g. methoxycarbonylmethyl or carboxymethyl,alkyl substituted by alkoxy e.g. methoxyethyl, 2,2-dimethoxyethyl, alkylsubstituted by hydroxy e.g. hydroxyethyl or alkyl substituted bydialkylamino e.g. dimethylaminoethyl, 2-benzyloxyphenyl,dimethoxybenzyl, optionally substituted heteroarylmethyl e.g.2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,3-methylimidazolylmethyl, heteroaryl such as thiazolyl e.g.2-1,3-thiazolyl, alkyl substituted by NR₇R₈ [wherein NR₇R₈ form a6-membered heterocyclic ring (e.g. piperidinoethyl or morpholinoethyl)],cycloalkyl e.g. cyclopropyl or cyclohexyl, or NR₅R₆ represents,azetidino, 3-hydroxyazetidino, 3-methoxyazetidino, pyrrolidino,piperidino, 4-dimethylaminopiperidino, 4-methyl 1,4-diazepan-1-yl,morpholino, an optionally substituted piperazino ring e.g.N-methylpiperazino, N-methanesulphonylpiperazino,N-2-methoxyethylpiperazino, thiomorpholino or the sulphoxide or sulphonethereof.

A preferred class of compounds of the invention are those of formula(1a) wherein R₁ is 2-indanyl, R₂ is a group selected from 1-methylpropylor 2-methylpropyl and R₄ is hydroxy and/or more particularly the groupNR₅R₆.

A further preferred class of compounds of the invention are those offormula (1a) wherein R₅ is a group selected from hydrogen, C₁₋₄alkyle.g. methyl or C₁₋₄alkoxyC₂₋₄alkyl e.g. 2-methoxyethyl and R₆ is a groupselected from hydrogen, C₁₋₄alkoxy e.g. methoxy, C₁₋₄alkyl e.g. methyl,n-propyl, isopropyl or t-butyl, C₁₋₄ alkyl substituted by 1 to 3 halogenatoms e.g. 2,2,2-trifluoroethyl or 2-fluoroethyl, C₁₋₄alkyl substitutedby alkoxycarbonyl or carboxyl e.g. methoxycarbonylmethyl orcarboxymethyl, alkyl substituted by alkoxy e.g. methoxyethyl,2,2-dimethoxyethyl, alkyl substituted by hydroxy e.g. hydroxyethyl oralkyl substituted by dialkylamino e.g. dimethylaminoethyl,2-benzyloxyphenyl, dimethoxybenzyl, optionally substitutedheteroarylmethyl e.g. 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,3-methylimidazolylmethyl, heteroaryl such as thiazolyl e.g.2-1,3-thiazolyl, alkyl substituted by NR₇R₈ [wherein NR₇R₈ form a6-membered heterocyclic ring (e.g. piperidinoethyl or morpholinoethyl)],cycloalkyl e.g. cyclopropyl or cyclohexyl, or NR₅R₆ represents,azetidino, 3-hydroxyazetidino, 3-methoxyazetidino, pyrrolidino,piperidino, 4-dimethylaminopiperidino, 4-methyl 1,4-diazepan-1-yl,morpholino, an optionally substituted piperazino ring e.g.N-methylpiperazino, N-methanesulphonylpiperazino,N-2-methoxyethylpiperazino, thiomorpholino or the sulphoxide or sulphonethereof.

A yet further preferred class of compounds of the invention are those offormula (1a) wherein R₃ is a group selected from phenyl, halophenyl suchas 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl,3-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 2,3-difluorophenyl,3,4-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl,2,5-difluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 2 fluoro-4-bromophenyl, 4-chloro-3-fluorophenyl2,3,4-trifluorophenyl 2,4,5-trifluorophenyl or 2,4,6-trifluorophenyl,2-fluoro-4,5-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl,4-fluoro-3-methoxyphenyl, 2-fluoro-4 methoxyphenyl, 2-fluoro-4hydroxyphenyl, 2-fluoro-4-dimethylaminomethylphenyl,2-fluoro-4-hydroxymethylphenyl, 3-fluoro-4-(4-morpholino)phenyl,3-fluoro-4-carboxymethyloxyphenyl,3-fluoro-4-t-butyloxycarbonylmethyloxyphenyl,3-fluoro-4-dimethylaminocarbonyloxyphenyl, 3-chloro-4trifluoromethoxyphenyl, 2,3-difluoro-4-methyl-phenyl,4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl,4-methoxyphenyl, 4-methoxycarbonylphenyl, 3-methoxycarbonyphenyl,4-methylsulphonylphenyl, 4-methylaminocarbonylphenyl,4-aminocarbonylphenyl, 4-methylaminosulphonylphenyl,3-(3-pyrazyolyl)phenyl, 4-(3-pyrazolyl)phenyl, 4-(4-pyrazolyl)phenyl,4-(3-pyridyl)phenyl, 4-(2-pyridylphenyl), 4-(2-imidazolyl)phenyl,3-(2-imidazolyl)phenyl, 4-(1-t-butyl-tetrazol-5-yl)phenyl,4-methylaminophenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl,4-acetylaminophenyl, 3-acetylaminophenyl, 4-hydroxy-3-acetylaminophenyl,4-methylsulphonylaminophenyl, 4-N-methylpiperazinophenyl,4-N-pyrrolidinophenyl, 2-fluoro-4-(4-morpholino)phenyl,4-(4-morpholino)phenyl, 4-(4-hydroxypiperidino)phenyl,2-fluoro-4-(4-hydroxypiperidino)phenyl, 3-(1-pyrazolyl)phenyl,4-(1-pyrazolyl)phenyl, 4-(1-3,5 di-t-butylpyrazolyl)phenyl,3-(1-imidazolyl)phenyl, 4-(1-imidazolyl)phenyl,4-(1-1,2,4-triazolyl)phenyl, 4-(1-1,2,3-triazolyl)phenyl,4-(2-4,-t-butylthiazolyl)phenyl, 4-(5-2-t-butyltetrazolyl)phenyl, 4-(4spiro-1,3-dioxolanyl)piperidinophenyl, 4-(4-fluorophenyl)phenyl,4-(4-ethylaminosulphonylphenyl)phenyl, 4-dimethylaminoethoxyphenyl,3-(dihydroxyboryl)phenyl, 2-furanyl, 3-thienyl, 3-furanyl, 2-thienyl,4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chloro-2-thienyl,3-fluoro-5-methyl-2-thienyl, 5-methyl-2-thienyl, 5-methyl-2-furanyl,5-bromo-2-furanyl, 4,5-dimethyl-2-furanyl, 5-trifluoromethyl-2-furanyl,2-furanyl-4-carboxylic acid methylamide, 2-furanyl-5-carboxylic acidmethylamide, 2-pyridyl, 6-methyl-2-pyridyl, 6-methyl-3-pyridyl,6-methoxy-3-pyridyl, 6-hydroxy-3-pyridyl, 6-trifluoromethyl-3-pyridyl,3-pyridyl, 4-pyridyl, 3,5-pyrimidinyl, 2-thiazolyl, 2-methyl-4-oxazolyl,2-ethyl-4-oxazolyl, 2-cyclopropyl-4-oxazolyl,2-trifluoromethyl-4-oxazolyl, 2,5-dimethyl-4-oxazolyl, 4-thiazolyl,2-methyl-4-thiazolyl, 2-trifluoromethyl-4-thiazolyl,2-trifluoromethyl-5-thiazolyl, 1-methyl-4-pyrazolyl,1,3-dimethyl-5-pyrazolyl, 5-(2-pyridyl)-2-thienyl,2,3-dihydro-1-benzofuran-5-yl, 1,3-benzodioxol-5-yl,1H-1,2,3-benzotriazol-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl,2,2-difluoro-1,3-benzodioxol-5-yl, 1,3-benzothiazol-6-yl,1-methyl-1H-1,2,3-benzotriazol-5-yl,1-methyl-1H-1,2,3-benzotriazol-6-yl, 1,2,3-benzothiadiazol-6-yl,2-methyl-1,3-benzoxazol-5-yl, 2-methyl-1,3-benzoxazol-6-yl,1-benzofuran-5-yl, 1-methyl-1H-lindol-5-yl, 1-benzothien-5-yl,1-benzofuran-6-yl, 1H-indol-6-yl, 1-methyl-1H-benzimidazol-6-yl,1-methyl-1H-benzimidazol-5-yl, 3-methyl-1,2-benzoisoxazol-5-yl,2-fluoro-1-benzofuran-5-yl, 1H-indol-5-yl, 2-methyl-1H-benzofuran-5-yl,1H-indazol-5-yl, 1H-indazol-6-yl, 1-benzofuran-2-yl or1-methyl-1H-benzimidazol-2-yl.

Particular preferred compounds of the invention include:

-   (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide-   (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide-   (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-morpholinamide-   (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide.-   (2R)—N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(4-hydroxypiperidin-1-yl)phenyl]ethanamide.-   (2R)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1R)-1-methylpropyl]-2,5-dioxopiperazin-1-yl}-2-(2-fluoro-4-morpholin-4-ylphenyl)-N-isopropylethanamide.-   (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide.-   (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide.-   (2R)—N-cyclopropyl-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide.-   (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methylethanamide-   (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide-   (3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione-   (3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione-   (3R,6R)-1-[(1R)-2-azetidin-1-yl-1-(2,4-difluorophenyl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione-   (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyethyl)-N-methylethanamide-   (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methyl-N-[2-(methylsulfonyl)ethyl]ethanamide-   (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)ethanamide-   (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methyl-N-(pyridin-2-ylmethyl)ethanamide-   (3R,6R)-1-{(1R)-1-(2,4-difluorophenyl)-2-[4-(methylsulfonyl)piperazin-1-yl]-2-oxoethyl}-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione-   (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methoxy-N-methylethanamide-   (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoic    acid-   methyl    (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-H-inden-2-yl)-6-isobutyl-2,5    dioxopiperazin-1-yl]ethanoate-   propyl    (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate-   1-(acetyloxy)ethyl    (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate-   (2R)—N-(tert-butyl)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1R)-1-methylpropyl]-2,5-dioxopiperazin-1-yl}ethanamide-   (2R)—N-(tert-butyl)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxopiperazin-1-yl}ethanamide-   (3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]piperazine-2,5-dione.-   (3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1R)-1-methylpropyl]piperazine-2,5-dione.-   (3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-(3-fluoroazetidin-1-yl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione.-   (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide.-   (2S)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-(5-methylthien-2-yl)ethanamide.-   (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide.-   (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-(2-methyl-1,3-oxazol-4-yl)ethanamide.-   (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione.-   (2S)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-(5-methylthien-2-yl)ethanamide-   (2S)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(3-fluoro-5-methylthien-2-yl)-N,N-dimethylethanamide-   (2R)-2-(1-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide.-   (2R)-2-(1,2,3-benzothiadiazol-6-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide.-   (2R)-2-(2,3-dihydro-1-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide.-   (2R)-2-(1,3-benzodioxol-5-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide.-   (2R)-2-(benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide.-   (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-(2-methyl-1-benzofuran-5-yl)ethanamide.-   (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-(2-methyl-1-benzofuran-5-yl)ethanamide.-   (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-1-[(1R)-1-(2-methyl-1-benzofuran-5-yl)-2-morpholin-4-yl-2-oxoethyl]piperazin-2,5-dione.-   (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(2-fluoro-1-benzofuran-5-yl)-N,N-dimethylethanamide.-   (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(2-fluoro-1-benzofuran-5-yl)-N-isopropylethanamide.-   (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2-fluoro-1-benzofuran-5-yl)-2-morpholin-4-yl-2-oxoethyl]-6-isobutylpiperazine-2,5-dione.-   (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(1H-indol-6-yl)-N,N-dimethylethanamide.-   (2R)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide.

The ability of the compounds of formula (I) to inhibit the actions ofoxytocin may be determined using a variety of conventional procedures.

Thus, compounds of formula (I) have a high affinity for the oxytocinreceptors on the uterus of rats and humans and this may be determinedusing conventional procedure. For example the affinity for the oxytocinreceptors on the rat uterus may be determined by the procedure ofPettibone et al, Drug Development Research 30. 129-142 (1993). Thecompounds of the invention also exhibit high affinity at the humanrecombinant oxytocin receptor in CHO cells and this may be convenientlydemonstrated using the procedure described by Wyatt et al. Bioorganic &Medicinal Chemistry Letters, 2001 (11) p 1301-1305.

The compounds of the invention are therefore useful in the treatment orprevention of diseases and/or conditions mediated through the action ofoxytocin. Examples of such diseases and/or conditions include pre-termlabour, dysmenorrhea and endometriosis.

The compounds may also be useful to delay labour prior to electivecaesarian section or transfer of the patient to a tertiary care centre.The compounds of the invention may also be useful for improvingfertility rates in animals, e.g. farm animals.

The invention therefore provides for the use of a compound of formula(I) and/or physiologically acceptable salts for use in therapy and inparticular use as medicine for antagonising the effects of oxytocin uponthe oxytocin receptor.

The invention also provides for the use of a compound of formula (I)and/or a physiologically acceptable salt thereof for the manufacture ofa medicament for antagonising the effects of oxytocin on the oxytocinreceptor.

According to a further aspect, the invention also provides for a methodfor antagonising the effects of oxytocin upon the oxytocin receptor,comprising administering to a patient in need thereof an antagonisticamount of a compound of formula (I) and/or a physiologically acceptablesalt thereof.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylactics as well as the treatment ofestablished diseases or symptoms.

It will further be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated, the route of administration and the age and thecondition of the patient and will be ultimately at the discretion of theattendant physician. In general however doses employed for adult humantreatment will typically be in the range of 2 to 800 mg per day,dependent upon the route of administration.

Thus for parenteral administration a daily dose will typically be in therange 2 to 50 mg, preferably 5 to 25 mg per day. For oral administrationa daily dose will typically be within the range 10 to 800 mg, e.g. 20 to150 mg per day.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example as two,three, four or more sub-doses per day.

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provides a pharmaceutical formulationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt or non-toxic metabolically labile esters thereof together with oneor more pharmaceutically acceptable carriers thereof and, optionally,other therapeutic and/or prophylactic ingredients. The carrier(s) mustbe ‘acceptable’ in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The compositions of the invention include those in a form especiallyformulated for oral, buccal, parenteral, inhalation or insufflation,implant or rectal administration.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example, syrup, acacia, gelatin,sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone;fillers, for example, lactose, sugar, microcystalline cellulose,maize-starch, calcium phosphate or sorbitol; lubricants, for example,magnesium stearate, stearic acid, talc, polyethylene glycol or silica;disintegrants, for example, potato starch or sodium starch glycollate,or wetting agents such as sodium lauryl sulphate. The tablets may becoated according to methods well known in the art. Oral liquidpreparations may be in the form of, for example, aqueous or oilysuspensions, solutions emulsions, syrups or elixirs, or may be presentedas a dry product for constitution with water or other suitable vehiclebefore use. Such liquid preparations may contain conventional additivessuch as suspending agents, for example, sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats; emulsifying agents, for example, lecithin, sorbitan mono-oleate oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters, propyleneglycol or ethyl alcohol; solubilizers such as surfactants for examplepolysorbates or other agents such as cyclodextrins; and preservatives,for example, methyl or propyl p-hydroxybenzoates or ascorbic acid. Thecompositions may also be formulated as suppositories, e.g. containingconventional suppository bases such as cocoa buffer or other glycerides.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The composition according to the invention may be formulated forparenteral administration by injection or continuous infusion.Formulations for injection may be presented in unit dose form inampoules, or in multi-dose containers with an added preservative. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilising and/or dispersing agents. Alternatively theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile, pyrogen-free water, before use.

The compositions according to the invention may contain between 0.1-99%of the active ingredient, conveniently from 30-95% for tablets andcapsules and 3-50% for liquid preparations.

Compounds of formula (I) wherein R₄ is the group NR₅R₆ may be preparedby cyclisation of the compound of formula (II)

wherein R₁, R₂ and R₃ have the meanings defined in formula (I) R₁₁ ishydrogen and R₁₂ is a C₁₋₃alkyl group (e.g. methyl) in a suitablesolvent such as an alkanol e.g. methanol and/or 2,2,2-trifluoroethanol,dioxan or a mixture thereof or a halohydrocarbon e.g. dichloromethane.

The compound of formula (II) wherein R₁₁ is hydrogen is convenientlyprepared in-situ by treating a compound of formula (II) wherein R₁₁ isan acid labile nitrogen protecting group and R₁₂ is hydrogen orC₁₋₃alkyl, with an acid in a suitable solvent followed by treatment witha hydrohalic acid and methanol if R₁₂ in the starting material ishydrogen, and then addition of a suitable base e.g. triethylamine or bytreating a compound of formula (II) wherein R₁₁ is an hydrogenolysablenitrogen protecting group and R₁₂ is C₁₋₃alkyl in a suitable solventsuch as methanol or 2,2,2-trifluoroethanol with hydrogen in the presenceof a suitable catalyst e.g. palladium on carbon.

Examples of suitable nitrogen protecting groups R₁₁ includealkoxycarbonyl e.g. t-butyloxycarbonyl or an optionally substitutedbenzyloxycarbonyl group. When R₁₂ is C₁₋₃alkyl this is convenientlyethyl or more particularly methyl. Examples of a suitable acids includemineral acids such as hydrohalic acids e.g. hydrochloric acid or organicacids such as trifluoroacetic acid. The reaction is conveniently carriedout in a solvent such as 1,4-dioxan or an alkanol e.g. methanol or amixture thereof, or halohydrocarbon e.g. dichloromethane.

The compounds of formula (II) may be prepared by reaction of the mixedanhydride (III)

wherein R₁ and R₁₁ have the meanings defined above and wherein R₁₃ is aC₁₋₆ straight or branched chain alkyl, optionally substituted phenyl orbenzyl group, with the amine (IV)

wherein R₂, R₃, R₅ and R₆ have the meanings defined above, and R₁₂ ishydrogen.

The reaction is preferably carried out in an aprotic solvent such as anether e.g. tetrahydrofuran or a tertiary amide such asN,N-dimethylformamide or a mixture thereof. The compounds of formula(III) may be prepared by treating the N-protected amino acid (V)

wherein R₁ and R₁₁ have the meanings defined above with thecorresponding haloformate (VI; R₁₃CO₂X wherein R₁₃ has the meaningdefined in formula (III) and X is halogen e.g. chlorine, or bromine) inthe presence of a suitable tertiary organic amine e.g.N-methylmorpholine and in an aprotic solvent e.g. an ether such astetrahydrofuran or a hydrocarbon e.g. toluene.

The amine (IV) wherein R₅ is hydrogen may be prepared treating the aminoacid (VII)R₁₂O₂CCH(R₂)NH₂  (VII)wherein R₂ has the meanings defined above and R₁₂ is hydrogen with thealdehyde (VIII; R₃CHO wherein R₃ has the meaning defined in formula (I))in a suitable solvent such as an alkanol e.g. methanol followed byreaction with the isonitrile (IX; R₆N═C wherein R₆ has the meaningsdefined in formula I other than hydrogen). Alternatively, the compoundsof formula (II) wherein R₁, R₂ and R₃ have the meanings given in formula(I) and R₁₁ is a nitrogen protecting group and R₁₃ is a carboxylprotecting group may be prepared by reacting the amino acid derivative(VII) wherein R₂ has the meaning given in formula (I) and R₁₂ is acarboxyl protecting group with the aldehyde (VIII) wherein R₃ has themeaning given in formula (I) in a solvent such as an alkanol e.g.methanol or 2,2,2-trifluoroethanol followed by the sequential additionof the amino acid (V) wherein R₁ has the meanings given in formula (I)and R₁₁ is a carboxyl protecting group and the isonitrile (IX) whereinR₆ has the meanings given in formula (I).

Compounds of formula (II) wherein R₁₂ is a C₁₋₃alkyl group may also beprepared by reacting the carboxylic acid (X) or an activated derivativethereof

wherein R₁, R₂, R₃ and R₁₁ have the meanings defined above and R₁₂ is aC₁₋₃alkyl group, with the amine NHR₅R₆ wherein R₅ and R₆ have themeanings defined in formula (I). Examples of a suitable activatedderivative of the carboxylic acid (X) include those commonly used inpeptide synthesis e.g. that derived from reaction ofbenzotriazol-1-yloxytri-pyrrolidinophosphonium hexafluorophosphate inthe presence of a suitable amine such as disopropylethylamine.

The carboxylic acid (X) may be prepared from the corresponding compoundof formula (II) wherein R₅ represents hydrogen and R₆ represents the2-hydroxyphenyl by reaction with carbonyldiimidazole orthiocarbonyldimidazole in a suitable solvent such as dichloromethane andsubsequent reaction of the product thus formed with aqueous acetone.

Compounds of formula (II) wherein R₆ represents 2-hydroxyphenyl areconveniently prepared by catalytic hydrogenolysis (e.g. Pd/H₂) of thecorresponding compound wherein R₆ is a 2-benzyloxyphenyl group.

In a further aspect of the invention compounds of formula (I) as definedabove may be converted into other compounds of formula (D). Thuscompounds of formula (I) wherein R₄ is hydroxyl maybe prepared from acompound of formula (D) wherein R₄ is the group NR₅R₆ and R₅ is hydrogenR₆ is 2-hydroxyphenyl by reaction with carbonyldiimidazole orthiocarbonyldiimidazole in a suitable solvent such as dichloromethaneand subsequent reaction of the product thus formed with aqueous acetone.

Compounds of formula (I) wherein R₅ is hydrogen and R₆ is2-hydroxyphenyl may be from the corresponding compound of formula (I)wherein R₆ is a 2-benzyloxyphenyl group by hydrogenolysis using hydrogenand a palladium catalyst.

Compounds of formula (I) wherein R₄ is the group NR₅R₆ may be preparedby reaction of the compound of formula (I) wherein R₄ is hydroxyl or anactivated derivative thereof with the amino NHR₅R₆ wherein R₅ and R₆have the meaning defined in formula (I) under the standard condition forpreparing amides from a carboxylic acid and an amine such as NHR₅R₆.

Thus the amides may be prepared by treating the compound of formula (I)wherein R₄ is hydroxyl with an activating agent such as BOP(benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate), TBTU(2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate),BOP—Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride) or oxalyl chloridein an aprotic solvent such as dichloromethane optionally in the presenceof a tertiary amine such as triethylamine and subsequent reaction of theproduct thus formed with the amine NHR₅R₆.

Alternatively compounds of formula (I) wherein R₄ is the group NR₅R₆ maybe prepared by reacting a compound of formula (I) wherein R₅ is hydrogenand R₆ is 2-hydroxyphenyl with carbonyldiimidazole orthiocarbonyldiimidazole in a suitable solvent such as dichloromethaneand subsequent reaction of the product thus formed with the amine NHR₅R₆

Compounds of formula (I) wherein R₄ is OC₁₋₄ alkyl (optionallysubstituted with C₁₋₄alkylcarbonyloxy) may be prepared by reacting thecorresponding carboxylic acid (R₄ is OH) or an activated derivativethereof with the appropriate alcohol (R₄OH) or alkyl halide (R₄ halide)under standard conditions for preparing such esters. Suitable activatedderivatives include the acid halides, mixed anhydrides, those formedwith coupling reagents commonly used in peptide synthesis e.g.carbonyldiimidazole and base salts of the acid e.g. alkali metal salts.

Compounds of formula (IV) may be converted into other compounds offormula (IV) using standard procedures. Thus compound of formula (IV)wherein R₅ is hydrogen and R₆ is 2-benzyloxyphenyl may be converted intoother compounds of formula (IV) wherein R₅ and R₆ have other meanings asdefined in formula (I) using the same procedures as described above forcarrying out analogous reactions on compounds of formula (1).

Compounds of formula (I) wherein the stereochemistry of any of thesubstituents R₁, R₂ and R₃ is as shown in formula (1a) may be preparedstarting from the corresponding single isomers of the intermediates(III), (IV) and (VII) and/or the various isomeric mixtures may beseparated by conventional procedures.

The intermediates (V), (VI), (VII), (VIII) and (IX) are either knowncompounds may be prepared by analogous methods to those known forpreparing structurally related compounds.

Compounds of formula group (I) wherein R₄ is OH may be prepared bycyclisation of a corresponding compound of formula (II) under theconditions described above for preparing compounds of formula (I).

Physiologically acceptable salts of a compound of formula (I) wherein R₄is OH or one of the groups R₁, R₂, R₃ or NR₄R₅ has a basic or acidiccentre may be prepared by treating the said base or acid with therequired physiologically acceptable acid or base and this reaction isconveniently carried out in a solvent for the said compound of formula(I). Physiologically acceptable derivatives of a compound of formula (I)may be prepared from the appropriate intermediate corresponding toformula (II) using the process described above for preparing compoundsof formula (I) or directly from the compounds of formula (I) byconventional procedures for preparing such derivatives. Thusmetabolically labile esters may be prepared by esterification of thefree carboxyl or hydroxyl group using standard esterificationtechniques.

The following examples are illustrative, but not limiting of theembodiments of the present invention.

General Purification and Analytical Methods

Analytical HPLC was conducted on a Supelcosil LCABZ+PLUS column (3.3cm×4.6 mm ID), eluting with 0.1% HCO₂H and 0.01 M ammonium acetate inwater (solvent A), and 0.05% HCO₂H 5% water in acetonitrile (solvent B),using the following elution gradient 0-0.7 minutes 0% B, 0.7-4.2 minutes0%-100% B, 4.2-5.3 minutes 100% B, 5.3-5.5 minutes 0% B at a flow rateof 3 ml/minute. The mass spectra (MS) were recorded on a Fisons VGPlatform spectrometer using electrospray positive [(ES+ve to give MH⁺and M(NH₄)⁺ molecular ions] or electrospray negative [(ES-ve to give(M−H)⁻ molecular ion] modes on a Micromass series 2 or a Waters ZQ massspectrometer. ¹H NMR spectra were recorded using a Bruker DPX 400 MHzspectrometer using tetramethylsilane as the external standard. Biotage™chromatography refers to purification carried out using equipment soldby Dyax Corporation (either the Flash 40i or Flash 150i) and cartridgespre-packed with KPSil. Mass directed autoprep refers to methods wherethe material was purified by high performance liquid chromatography on aHPLCABZ+5 μm column (5 cm×10 mm i.d.) with 0.1% HCO₂H in water and 95%MeCN, 5% water (0.5% HCO₂H) utilising gradient elution at a flow rate of8 ml minutes⁻¹. The Gilson 202-fraction collector was triggered by a VGPlatform Mass Spectrometer on detecting the mass of interest.

Hydrophobic frits refer to filtration tubes sold by Whatman. SPE (solidphase extraction) refers to the use of cartridges sold by InternationalSorbent Technology Ltd. TLC (thin layer chromatography) refers to theuse of TLC plates sold by Merck coated with silica gel 60 F₂₅₄. Oasis™refers to Waters® Oasis™ HLB Extraction Cartridges, sold by WatersCorporation®.

METHOD 1 Example 1(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide

To a solution of (D)-leucine methyl ester hydrochloride (300 mg) inmethanol (4 ml) was added triethylamine (230 μl) and4-fluorobenzaldehyde (177 μl). The mixture was stirred for 2.5 hoursbefore(2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoicacid (481 mg) and isopropylisocyanide (225 μl) were sequentially added.After stirring for 16 hr, the solvent was removed in vacuo and theresidue was dissolved in chloroform. This solution was washed with asaturated aqueous sodium carbonate solution (×2), aqueous citric acid(0.5M, ×2) and brine (×1), dried over magnesium sulphate and evaporatedin vacuo. The residue was dissolved in dichloromethane (2 ml) andtrifluoroacetic acid (5 ml) and stirred for 3 hours at ambienttemperature. After this time, the solvent was removed in vacuo and theresidue co-evaporation with toluene (×3) and cyclohexane/ether (1:1,×2). The residue was treated with a solution of triethylamine in dioxane(2% solution, 10 ml) and was left to stir overnight. After this time,the dioxane was removed in vacuo and the residue was dissolved in ethylacetate. The solution was washed with citric acid solution (0.5M, ×2),saturated aqueous sodium bicarbonate solution (×1) and brine (×1). Theliquors were then dried over magnesium sulphate and in vacuo and werethen co-evaporated with cyclohexane:ether (1:1, ×2). This crude materialwas purified by Biotage™ (90 g, silica) eluting with toluene: ethylacetate:cyclohexane (5:3:2) with 5% triethylamine to give(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide(149 mg)

HPLC Rt=3.42 minutes; m/z [M+H]⁺=480.

¹H NMR (CDCl₃) δ 7.44 (m, 2H), 7.22 (m, 2H), 7.16 (m, 2H), 7.11 (t, 2H),6.50 (d, 1H), 5.60 (d, 1H), 5.11 (s, 1H), 4.10 (m, 1H), 3.96 (m, 2H),3.16 (dd, 1H), 3.07 (d, 1H), 2.91 (m, 1H), 2.77 (m, 1H), 1.84 (m, 1H),1.73 (m, 1H), 1.42 (m, 1H), 1.13 (d, 3H), 1.12 (d, 3H), 0.84 (d, 3H),0.79 (d, 3H)

Similarly prepared

Example 2(2R)—N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(4-hydroxypiperidin-1-yl)phenyl]ethanamide

HPLC Rt=3.27 minutes; m/z [M+H]⁺=575.

(CDCl₃)

7.3 (d, 2H), 7.2 (m, 2H), 7.15 (m, 2H), 6.9 (d, 2H), 6.1 (d, 1H), 5.5(s, 1H), 5.15 (s, 1H), 3.95 (m, 2H), 3.9 (m, 1H), 3.6 (m, 2H), 3.15 (m,1H), 3.1 (m, 2H), 3.0 (m, 2H), 2.9 (m, 1H), 2.75 (m, 1H), 2.0 (m, 2H),1.75 (m, 1H), 1.65 (m, 3H), 1.45 (m, 1H), 1.3 (s, 9H), 0.8 (d, 3H), 0.7(d, 3H).

Example 3(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1R)-1-methylpropyl]-2,5-dioxopiperazin-1-yl]-2-(2-fluoro-4-morpholin-4-ylphenyl)-N-isopropylethanamide

HPLC Rt=3.34 minutes; m/z [M+H]⁺=565

¹H NMR (CDCl₃) δ 7.52 (t, 1H), 7.22-7.11 (m, 4H), 7.04 (br s, 1H), 6.66(dd, 1H), 6.56 (dd, 1H), 5.07 (s, 1H), 4.19-4.08 (m, 2H), 3.98 (dd, 1H),3.86-3.81 (4H, m), 3.21-2.91 (m, 8H), 2.80-2.73 (m, 1H), 1.96-1.86 (m,1H), 1.72-1.61 (m, 1H), 1.51-1.40 (m, 1H), 1.19 (d, 3H), 1.16 (d, 3H),1.06 (d, 3H), 0.92 (t, 3H).

METHOD 2 Example 4(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide

Methyl(2R)-2-{[(1R,S)-2-{[2-(benzyloxy)phenyl]amino}-1-(4-fluorophenyl)-2-oxoethyl][(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino}-4-methylpentanoate

A mixture of 4-fluorobenzaldehyde (1.2 g), (D)-leucine methyl esterhydrochloride (1.7 g), triethylamine and methanol (56 ml) was stirred atroom temperature for 3 hours. 2-Benzyloxyphenylisocynanide (2.0 g) andN-tert-butoxycarbonyl-(D)-indanyl glycine (2.77 g) were then addedsequentially. After 40 hours the reaction mixture was partitionedbetween 2M hydrochloric acid and ethyl acetate. The separated organiclayer was washed with a saturated aqueous sodium bicarbonate solutionand brine, dried over magnesium sulphate and evaporated in vacuo. Theresultant crude material was purified by column chromatography (elutingwith 0.5% and 0.2% methanol/dichloromethane) to afford methyl(2R)-2-{[(1R,S)-2-{[2-(benzyloxy)phenyl]amino}-1-(4-fluorophenyl)-2-oxoethyl][(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino}-4-methylpentanoate(4.3 g)

HPLC Rt=4.34 minutes, m/z [M+H]⁺=752

MethylN-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]-N-{(1R,S)-1-(4-fluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-D-leucinate

A mixture of methyl(2R)-2-{[(1R,S)-2-{[2-(benzyloxy)phenyl]amino}-1-(4-fluorophenyl)-2-oxoethyl][(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino}-4-methylpentanoate(560 mg), palladium on carbon (70 mg) and ethanol (15 ml) was stirredunder an atmosphere of hydrogen for 5 hours. The mixture was filteredthrough Celite and the filtrate was evaporated in vacuo. The crudeproduct was purified by column chromatography (silica) eluting withethyl acetate: cyclohexane (10% to 15%) to give methylN-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]-N-{(1R,S)-1-(4-fluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-D-leucinate.

HPLC Rt=4.06 minutes, m/z [M+H]⁺=662

(2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl][(1R)-1-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoicacid

Carbonyldiimidazole (558 mg) was added to a solution of methylN-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]-N-{(1R,S)-1-(4-fluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-D-leucinate(2.0 g) in dichloromethane (20 ml) and the resultant mixture was stirredat room temperature for 24 hours. The reaction was then concentrated todryness, dissolved in a mixture of acetone:water (60 ml:40 ml) andstirred for 17 hours at room temperature. The solution was thenpartitioned between 2M aqueous hydrochloric acid and ethyl acetate. Theseparated organic layer was washed with saturated aqueous sodiumbicarbonate solution and brine before being dried over magnesiumsulphate and evaporated in vacuo. Half of the material was taken to beused crude in further experiments. The second half was purified byBiotage™ (silica, 90 g) eluting with methanol:dichloromethane:ammonia(1:98.5:0.5 to 2.5:86.5:1). Evaporation of the appropriate fractionsgave(2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl][(1R)-1-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoicacid. (173 mg).

HPLC Rt=3.91 minutes, m/z [M+H]⁺=571

(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide

A solution of(2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl][(1R)-1-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoicacid (73 mg) in N,N-dimethylformamide (2 ml) was sequentially treatedwith diisopropylethylamine (51 μL), phosphorus,(1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-(T-4)-hexafluorophosphate(80 mg) and then after 2 minutes, 2,2,2-trifluoroethylamine (25 μl).This reaction mixture was stirred for 2 hours before being partitionedbetween 2M aqueous hydrochloric acid and ethyl acetate. The organiclayer was washed with saturated aqueous sodium bicarbonate solution andbrine before being dried over magnesium sulphate and evaporated invacuo. The residue was dissolved in 4M hydrogen chloride in dioxane andstirred for 7 hours at room temperature. The reagent was removed invacuo and the residue partitioned between ethyl acetate and saturatedaqueous sodium bicarbonate solution. The separated organic fraction waswashed with brine before being dried over magnesium sulphate andevaporated in vacuo. The crude material was purified by columnchromatography (silica) eluting with methanol: dichloromethane (1% to3%) to furnish((2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide(10 mg)

HPLC Rt=3.4 minutes, m/z [M+H]⁺=520

¹H NMR (CDCl₃) δ 7.42 (m, 2H), 7.34 (d, 1H), 7.20-7.10 (m, 6H), 6.61 (t,1H), 5.28 (s, 1H), 4.08-3.96 (m, 3H), 3.88 (m, 1H), 3.14 (dd, 1H), 3.02(m, 2H), 2.95-2.77 (m, 2H), 1.88-1.70 (m, 2H), 1.40 (ddd, 1H), 0.85 (d,3H), 0.79 (d, 3H).

The following compounds were prepared in a similar manner

Example 5(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

HPLC Rt=3.37 minutes, m/z [M+H]⁺=466

1H NMR (CDCl₃); δ 7.47-7.40 (m, 2H), 7.25-7.12 (m, 6H), 6.50 (d, 1H),6.47 (s, 1H), 4.15 (dd, 1H), 3.98 (dd, 1H), 3.21-3.01 (m, 3H), 2.99 (s,3H), 2.92-2.73 (m, 2H), 2.83 (m, 3H), 1.59-1.49 (m, 1H), 1.42 (dt, 1H),0.66-0.57 (m, 1H), 0.62 (d, 3H), 0.40 (d, 3H).

Example 6(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-morpholinamide

HPLC Rt=3.32 minutes, m/z [M+H]⁺=508

1H NMR (CDCl3); δ 7.44-7.39 (m, 2H), 7.26-7.12 (m, 6H), 6.87 (d, 1H),6.51 (s, 1H), 4.12 (dd, 1H), 4.00 (dd, 1H), 3.73-3.62 (m, 3H), 3.60-3.54(m, 2H), 3.37 (m, 1H), 3.23 (m, 1H), 3.20-3.02 (m, 4H), 2.91-2.75 (m,2H), 1.60-1.50 (m, 1H), 1.45 (dt, 1H), 0.63 (d, 3H), 0.62-0.55 (m, 1H),0.42 (d, 3H).

The 2-fluoro-4-(morpholino)-benzaldehyde used in this synthesis wasprepared by the following procedure.

2-Fluoro-4-(morpholino)-benzonitrile

A solution of 2,4-difluorobenzonitrile (6.03 g, 43.35 mmol) andmorpholine (8.3 ml, 95.17 mmol) in tetrahydrofuran (27 ml) was stirredat room temperature for 24 hr. The mixture was evaporated and the whitesolid purified by Biotage™ column (90 g, silica) eluting withcyclohexane:ethyl acetate: (4:1) to give2-fluoro-4-(morpholino)-benzonitrile as a white solid (5.81 g, 65%).

HPLC Rt=2.83 minutes; m/z [M+H]⁺=207.

2-Fluoro-4-(morpholino)-benzaldehyde

To a solution of 2-fluoro-4-(morpholino)-benzonitrile (2.82 g, 13.7mmol) in tetrahydrofuran (27 ml) under a nitrogen atmosphere was addeddropwise a 1.5 M solution of DIBAL-H in toluene (18.3 ml, 27.3 mmol)during 13 minutes and the resulting mixture stirred for 23.5 hr at roomtemperature. The mixture was cooled to −50° C. and the excess DIBAL-Hdestroyed by careful addition of methanol (27 ml). The mixture was thenstirred at room temperature for 10 mins, saturated ammonium chloride (27ml) added and the resulting mixture stirred at room temperature for 40mins., and then evaporated under reduced pressure to a yellow solid.This solid was partitioned between dichloromethane (120 ml) and water(120 ml) and solid potassium carbonate added until the aqueous phase waspH 10. The phases were separate via a hydrophobic frit and the organicphase evaporated and the residue purified by a Biotage™ column (40 g,silica) eluting with cyclohexane:ethyl acetate: (7:3) to give2-fluoro-4-(morpholino)-benzaldehyde (1.96 g, 68%) as a white solid.

HPLC Rt=2.63 minutes; m/z [M+H]⁺=210.

METHOD 3 Example 7(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide

MethylN-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucinate

To a stirred suspension of (L)-Leucine (1.3 g) in methanol (100 ml)under a nitrogen atmosphere was added 2,4-difluorobenzaldehyde (1.42 g).After stirring at ambient temperature for 3 days, the suspension wascooled to −30° C. and a solution of isopropylisocyanide (0.691 g) inmethanol (5 ml) was added. After 3 hours at −30° C. the reaction wasallowed to warm to room temperature and was stirred for a further 20hours. The solvent was removed in vacuo, the residue purified using aBiotage™ column (40 g, silica) eluting with cyclohexane:ethyl acetate(gradient from 8:1 to 1:1). The required fractions were combined andconcentrated in vacuo to furnish methylN-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucinate(1.326 g). ¹H NMR (CDCl₃) δ 7.32 (m, 1H), 6.88 (m, 1H), 6.82 (m, 1H),6.78 (m, 1H), 4.42 (s, 1H), 4.07 (m, 1H), 3.69 (s, 3H), 3.18 (t, 1H),1.66 (m, 1H), 1.49 (t, 2H), 1.18 (d, 3H), 1.15 (d, 3H), 0.88 (d, 3H),0.77 (d, 3H)

N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine

To a solution of methylN-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucinate(1.32 g) in methanol (15 ml) was added a solution of lithium hydroxide(294 mg) in water (15 ml). The reaction was rapidly stirred for 1.5hours and then evaporated in vacuo. The residue was dissolved in waterand neutralised using 2N hydrochloric acid. The resulting solid wascollected by filtration and dried in vacuo. The filtrate was applied to4 Oasis cartridges (6 g), which were eluted with water (×2) and methanol(×2). The required fractions were combined and concentrated in vacuo toaffordN-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine(1.01 g).

HPLC Rt=2.51 minutes; m/z [M+H]⁺=343.

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide

To a solution of(2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoicacid (291 mg) in dry tetrahydrofuran (5 ml) under a nitrogen atmosphereat −20° C. was added N-methylmorpholine (101 mg) and a solution ofisopropylchloroformate in toluene (1.0M, 1 ml). After 10 minutes, asolution ofN-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine(342 mg) in N,N-dimethylformamide/tetrahydrofuran (5 ml/10 ml) was addedand the resultant mixture was stirred at room temperature for 4 hours.The solvent was then removed in vacuo and the residue was treated with4N hydrochloric acid in dioxane (2 ml). After 4 hours, methanol (5 ml)was added to the reaction mixture and this was left to stand for 18hours. The solvent was then removed in vacuo and the residue waspurified on an SPE cartridge (50 g, silica) eluting withcyclohexane/ethyl acetate (gradient from 4:1 to neat ethyl acetate),which furnished the two diastereomers as white solids(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide;(0.137 g)

HPLC Rt=3.47 minutes, m/z [+H]⁺=498

¹H NMR (CDCl₃) δ 7.68 (m, 1H), 7.21 (m, 2H), 7.17 (m, 2H), 6.95 (m, 1H),6.89 (m, 1H), 6.79 (d, 1H), 5.91 (d, 1H), 5.33 (s, 1H), 4.12 (m, 1H),4.02 (m, 1H), 3.92 (dd, 1H), 3.16 (m, 1H), 3.05 (m, 2H), 2.90 (m, 1H),2.78 (m, 1H), 1.85 (m, 1H), 1.79 (m, 1H), 1.49 (m, 1H), 1.17 (m, 6H),0.88 (d, 3H), 0.82 (d, 3H)

METHOD 4 Example 8(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

MethylN-[(1R)-2-{[2-(benzyloxy)phenyl]amino}-1-(2,4-difluorophenyl)-2-oxoethyl]-L-leucinate

To a suspension of L-leucine (2.33 g) in methanol (200 ml) at −30° C.under nitrogen was added a solution of 2,4-difluorobenzaldehyde (2.52 g)in methanol (10 ml) and a suspension of 2-benzyloxyphenylisonitrile (3.7g) in methanol (40 ml). The reaction was stirred at −30° C. for 2.5hours and then allowed to warm to room temperature and stirred for afurther 6 days. The solvent was removed in vacuo and the residue waspassed through a Biotage™ column (90 g) eluting with cyclohexane:ethylacetate (8:1 and 7:1) to afford after evaporation of the appropriatefractions methylN-[(1R)-2-{[2-(benzyloxy)phenyl]amino}-1-(2,4-difluorophenyl)-2-oxoethyl]-L-leucinate(5.06 g).

HPLC Rt=4.0 minutes, m/z [M−H]⁻=495

MethylN-{(1R)-1-(2,4-difluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate

A mixture of palladium on carbon (10%, 300 mg), methylN-[(1R)-2-{[2-(benzyloxy)phenyl]amino}-1-(2,4-difluorophenyl)-2-oxoethyl]-L-leucinate(2.88 g) and ethyl acetate (30 ml) was stirred under a hydrogenatmosphere for 3 hours. The reaction was then filtered through Celiteand the filter pad was washed with further portions of ethyl acetate.The combined organic fractions were evaporated to give methylN-{(1R)-1-(2,4-difluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate(2.179 g).

HPLC Rt=3.52 min, m/z [M−H]⁻=405

MethylN-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate

A solution of methylN-{(1R)-1-(2,4-difluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate(203 mg) and 1,1′-thiocarbonyldiimidazole (100 mg) in dichloromethane (5ml) was left to stand for 18 hours. Water (10 □l) was added to thereaction mixture and this was then stirred rapidly for 30 minutes. Afterthis, 1H-Benzotriazolium, 1-[bis(dimethylamino)methylene]-,tetrafluoroborate(1-), 3-oxide (TBTU, 321 mg) and a solution ofdimethylamine in tetrahydrofuran (0.5 ml of 2M solution) were added. Thereaction mixture was stirred for a further 18 hours and was then passeddown an SPE (5 g, silica) eluting with a gradient (8:1 to 1:2cyclohexane:ethyl acetate). The required fractions were combined andevaporated to furnish methylN-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (100mg).

HPLC Rt=3.16 minutes m/z [M+H]⁺=343

N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine

To a solution of methylN-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (100mg) in methanol (3 ml) was added a solution of lithium hydroxide (15.4mg) in water (1 ml). After stirring vigorously for 4 hours the solventwas removed in vacuo. The residue was diluted with water (10 ml) thenneutralised with 2N hydrochloric acid. This solution was applied to anOasis™ cartridge (6 g) and eluted with water (×2) and methanol (×2). Therequired fractions were combined and evaporated to affordN-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (95mg).

HPLC Rt=2.23 minutes m/z [M+H]⁺=329

(2R)-2-(2,4-difluorophenol)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

To a solution of(2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoicacid (84 mg) in dry tetrahydrofuran (6 ml) at −20° C. under a nitrogenatmosphere was added N-methylmorpholine (32 □l) and a solution ofisopropylchloroformate in toluene (1.0M, 290 □l). After 10 minutes, asolution ofN-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (95mg) in tetrahydrofuran (10 ml) was added and the reaction was allowed towarm to room temperature. After 20 hours, the solvent was removed invacuo and the residue was dissolved in 4N hydrochloric acid in dioxan (4ml). After 4 hours methanol (5 ml) was added and the reaction was leftto stand for a further 18 hours. The solvent was then removed in vacuoand the residue was dissolved in dioxan (5 ml) and to this was addedtriethylamine (0.5 ml). After 1 hour, the solvent was removed and theresidue was applied to an SPE (10 g, silica). The product was elutedusing methanol. A second SPE was used to further purify the material (2g, silica) using an ethyl acetate: methanol gradient (20:1 to 1:1) toafford(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide(38 mg).

HPLC Rt=3.5 minutes, m/z [M+H]⁺=484

¹H NMR (CDCl₃) δ 7.42 (m, 1H), 7.22 (m, 2H), 7.17 (m, 2H), 7.02-6.90 (m,2H), 6.62 (s, 1H), 6.37 (m, 1H), 4.09 (m, 1H), 3.98 (dd, 1H), 3.20-3.02(m, 3H), 2.99 (s, 3H), 2.87 (m, 1H), 2.85 (s, 3H), 2.74 (m, 1H), 1.55(m, 2H), 0.70 (m, 1H), 0.67 (d, 3H), 0.41 (d, 3H)

Similarly prepared

Example 9(2R)—N-cyclopropyl-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide

HPLC Rt=3.41 minutes, m/z [M+H]⁺=496.

¹H NMR (CDCl₃) δ 7.67 (dt, 1H), 7.59 (1H, d), 7.21-7.11 (m, 4H),6.99-6.92 (m, 1H), 6.92-6.84 (m, 1H), 6.35 (d, 1H), 5.43 (s, 1H), 3.99(dd, 1H), 3.93 (dd, 1H), 3.17-2.71 (m, 6H), 1.88-1.70 (m, 2H), 1.48-1.38(m, 1H), 0.86 (s, 3H), 0.81-0.74 (m, 5H), 0.51-0.45 (m, 2H).

Example 10(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-benzyloxyphenyl)ethanamide

A mixture of 2,4-difluorobenzaldehyde (1.421 g), (D)-leucine methylester hydrochloride (1.817 g), triethylamine (1.391 ml) and methanol (20ml) was stirred at room temperature for 16 hours.N-tert-butoxycarbonyl-(D)-indanylglycine (2.914 g) and2-benzyloxy-phenylisocyanide (2.090 g) were then added sequentially.After 24 hours the solvent was removed under reduced pressure and thereaction mixture was taken up in dichloromethane (ca. 20 ml) andpurified by Biotage™ flash column chromatography (2×90 g silicacartridges on a Biotage Quad 3 system eluted with 1:9 ethylacetate:cyclohexane) to afford methyl(2R)-2-{[(1R,S)-2-{[2-(benzyloxy)phenyl]amino}-1-(2,4-difluorophenyl)-2-oxoethyl][(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino}-4-methylpentanoate(5.100 g) (HPLC Rt=4.40 minutes m/z [M+H]⁺=770). This was taken up in 4Mhydrogen chloride in 1,4-dioxane (20 ml) and the mixture was left atroom temperature for 3 hours. The solvent and hydrogen chloride wereblown off using a stream of nitrogen overnight. The crude material wastaken up in methanol (90 ml) containing triethylamine (10 ml). After 30minutes, the methanol and excess of triethylamine were removed underreduced pressure. The crude product was purified by Biotage™ flashcolumn chromatography (2×90 g silica cartridges on a Biotage Quad 3system eluted with 1:2 ethyl acetate:cyclohexane) to yield(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-benzyloxyphenyl)ethanamide(3.381 g).

HPLC Rt=3.99 minutes, m/z [M+H]⁺=638

(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide

(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-benzyloxyphenyl)ethanamide(3.381 g) was dissolved in ethyl acetate (200 ml) and hydrogenated atatmospheric pressure over 10% palladium on carbon catalyst (0.980 g of10% Pd/C:water 1:1 w/w) at room temperature for five hours. The reactionmixture was filtered through Celite and the solvent was removed underreduced pressure to give the(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamideas a cream-coloured foam (2.650 g).

HPLC Rt=3.61 minutes, m/z [M-H⁺]⁻=546 (no [M+H}⁺ visible)

(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-ethanoicacid

(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide(2.650 g) was stirred in dichloromethane (20 ml) and carbonyldiimidazole(1.178 g) was added. the mixture was left at room temperature for 16hours then the solvent was removed under reduced pressure. The residuewas then taken up in 1:1 acetone:water (v/v) (80 ml) and left at roomtemperature for 30 minutes. The bulk of the acetone was then removedunder reduced pressure and the residue was partitioned betweendichloromethane and 0.5M hydrochloric acid. The organic phase wasseparated (hydrophobic frit) and evaporated under reduced pressure. Thecrude product was purified (Biotage™ flash chromatography column, 90 gsilica cartridge eluted with (i) 1:1 ethyl acetate:cyclohexane (ii)ethyl acetate (iii) ethyl acetate:methanol 9:1) to afford(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-ethanoicacid as a colourless solid 1.524 g as a mixture of epimers.

HPLC Rt=3.44 and 3.58 minutes, both m/z [M+H⁺]=457

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

The acid(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-ethanoicacid (0.747 g) prepared as described above was dried over P₄O₁₀ in vacuofor five hours to give 0.724 g drier material; this was dissolved inanhydrous dichloromethane:acetonitrile (1:1 v/v, 6 ml) and treated withtriethylamine (0.223 ml) and BOP—Cl (bis(2-oxo-3-oxazolidinyl)phosphinicchloride, dissolved in anhydrous dichloromethane:acetonitrile (1:1 v/v,6 ml) and treated with triethylamine (0.223 ml) and BOP—Cl(bis(2-oxo-3-oxazolidinyl)phosphinic chloride, 0.450 g) and the mixturewas sonicated for ca. 1 min to give a gelatinous mass. After 10 minutesat room temperature a solution of dimethylamine in tetrahydrofuran (10ml of 2M solution) was added to give a clear solution; this was left for16 hours at room temperature. The solvents were removed under reducedpressure and the mixture was partitioned between dichloromethane and0.1M hydrochloric acid. The organic phase was separated (hydrophobicfrit) and evaporated under reduced pressure. The crude product waspurified by flash column chromatography (12 g Biotage™ silica cartridgeeluted with (i) 1:1 ethyl acetate:cyclohexane (ii) ethyl acetate (iii)ethyl acetate:methanol 9:1) to give the(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamideas a colourless solid 0.285 g.

HPLC Rt=3.43 minutes, m/z [M+H]⁺=484

¹H NMR (CDCl₃) δ 7.47-7.40 (m, 1H), 7.24-7.11 (m, 4H), 7.01-6.91 (m,3H), 6.62 (s, 1H), 4.09 (dd, 1H), 3.98 (dd, 1H), 3.19-3.01 (m, 3H), 2.99(3, 3H), 2.92-2.75 (m, 5H), 1.64-1.51 (m, 2H), 0.76-0.66 (m, 4H), 0.43(d, 3H).

METHOD 5 Example 11(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

(2R)-[(benzyloxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic Acid

R-Indanylglycine (1.91 g) was suspended in dioxane (10 ml) and water (10ml). To this was added triethylamine (1.7 ml) andN-(benzyloxycarbonyloxy)succinimide (2.54 g) and the reaction mixturewas stirred rapidly at room temperature for 2 days. The reaction mixturewas poured into water (50 ml) and extracted with chloroform (100 ml).The organic phase was washed with 1N hydrochloric acid (50 ml) and water(50 ml). This was dried over magnesium sulphate and the solvent removedin vacuo to give(2R)-[(benzyloxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid(3.06 g).

HPLC Rt=3.35 minutes; m/z [M+H]⁺=326.

¹H NMR (CDCl₃) δ 7.40-7.29 (m, 5H), 7.21-7.11 (m, 4H), 5.28 (d, 1H),5.11 (s, 2H), 4.57 (m, 1H), 3.14-2.79 (m, 5H).

(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide

To a solution of (D)-leucine methyl ester hydrochloride (1.45 g) inmethanol (10 ml) was added triethylamine (1.12 ml) and2,4-difluorobenzaldehyde (0.875 ml). The mixture was stirred for 3 daysbefore(2R)-[(benzyloxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid(2.6 g) and 2-benzyloxyphenylisocyanide (1.76 g) were sequentiallyadded. The reaction mixture was left to stand for 24 hours. The solventwas removed in vacuo and the residue was separated between ethyl acetate(200 ml) and water (200 ml). The organic phase was washed with brine. Tothis solution was added palladium on carbon (2.0 g) and acetic acid (10ml) and the reaction mixture was stirred under an atmosphere of hydrogenfor 2 hours. The mixture was filtered through Celite and washed withwater (3×100 ml), saturated sodium bicarbonate solution, brine and driedover magnesium sulphate. The solvent was evaporated in vacuo. The crudeproduct was purified by column chromatography (silica) eluting withethyl acetate: cyclohexane (50% to 66%) to give(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide(2.0 g).

HPLC Rt=3.59 minutes; m/z [M+H]⁺=548.

(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

Carbonyldiimidazole (4.80 g, 1.54 equiv.) was suspended in anhydrousdichloromethane (40 mL) and the suspension was left at room temperaturefor 15 minutes.(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide(10.50 g, pre-dried in vacuo over P₄O₁₀ for 24 hours) was then addedwith stirring and the resultant solution was stirred at room temperaturefor 6 hours. The resulting yellow solution was then treated with a 2.0Msolution of dimethylamine in tetrahydrofuran (54 mL, 5.6 equiv.) and theresulting mixture was stirred at room temperature for 16 hours. Thesolvents plus residual dimethylamine were removed under reduced pressureand the reaction mixture was taken up in dichloromethane (200 mL) andwashed with 1M hydrochloric acid (200 mL). The organic phase wasseparated using a hydrophobic frit and was evaporated under reducedpressure to ca. 50 mL. The crude product was applied to 4×90 g silicaBiotage™ columns on a Quad 3 system; each column being eluted with (i)2:1 v/v ethyl acetate:cyclohexane (12×50 mL fractions), (ii) ethylacetate (12×50 mL fractions), (iii) 9:1 v/v ethyl acetate:methanol togive(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide(5.753 g, 62%) as a colourless solid.

HPLC Rt=3.41 minutes, m/z [M+H]⁺=484

¹H NMR (CDCl₃) δ 7.48-7.38 (m, 2H), 7.24-7.11 (m, 4H), 7.01-6.90 (m,2H), 6.62 (s, 1H), 4.09 (dd, 1H), 3.98 (dd, 1H), 3.19-3.01 (m, 3H), 2.99(3, 3H), 2.92-2.75 (m, 5H), 1.64-1.51 (m, 2H), 0.76-0.66 (m, 4H), 0.43(d, 3H).

Similarly prepared:

Example 12(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methylethanamidecolourless solid, 41%

HPLC Rt=3.4 minutes, m/z [M+H]⁺=470

Example 13(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamideColourless Solid, 36%

HPLC Rt=3.3 minutes, m/z [M+H]⁺=456

Example 14(3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dioneColourless Solid, 61%

HPLC Rt=3.4 minutes, m/z [+H]⁺=526

Example 15(3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-(3-hydroxymazetidin-1-yl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dioneColourless Solid, 45%

HPLC Rt=3.2 minutes, m/z [M+H]⁺=512

(azetidin-3-ol prepared by the method of S S Chatterjee and D J Triggle;J. Chem. Soc. Chem. Comm. (2) 93 (1968)

Example 16(3R,6R)-1-[(1R)-2-azetidin-1-yl-1-(2,4-difluorophenyl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dioneColourless Solid, 46%

HPLC Rt=3.4 minutes, m/z [M+H]⁺=496

Example 17(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyethyl)-N-methylethanamideColourless Solid, 59%

HPLC Rt=3.3 minutes, m/z [M+H]⁺=514

Example 18(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methyl-N-[2-(methylsulfonyl)ethyl]ethanamideColourless Solid, 22%

HPLC Rt=3.2 minutes, m/z [M+H]⁺=576

Example 19(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)ethanamideColourless Solid, 11%

HPLC Rt=3.5 minutes, m/z [M+H]⁺=552 (2,2,2-trifluoroethylmethylaminehydrochloride was prepared by the method of E R Bissell and M Finger; J.Org. Chem. 24 1256-1259 (1959))

Example 20(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methyl-N-(pyridin-2-ylmethyl)ethanamidetan foam, 19%

HPLC Rt=3.5 minutes, m/z [M+H]⁺=561

Example 21(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methoxy-N-methylethanamide

HPLC Rt=3.4 minutes, m/z [M+H]⁺=500

Example 22(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoicAcid

Carbonyldiimidazole (1.42 g, 1.6 equiv.) was suspended in anhydrousdichloromethane (10 mL) and the suspension was left at room temperaturefor 15 minutes.(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide(3.00 g) was then added and the resultant solution was stirred at roomtemperature for 16 hours. The resulting yellow solution was thenevaporated under reduced pressure and the residue was treated with a 1:1(v/v) mixture of water and acetone (10 mL). The mixture was stirred for2 hours, then the acetone was removed under reduced pressure and theresidue was partitioned between dichloromethane and 0.1M HCl aq. Theorganic phase was separated using a hydrophobic frit then evaporated tolow volume and purified by chromatography on a Biotage Quad 3 system (90g silica column) eluted with 1:1 (v/v) ethyl acetate:cyclohexane, thenethyl acetate, then 1:1 (v/v) ethyl acetate:methanol to give a mixtureof diastereomers (2.61 g). These were separated on a chiralreverse-phase column (Chiralcel OD, eluted with 15% propan-2-ol/heptanecontaining 0.1% TFA) to give:(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoicacid (1.60 g)

HPLC Rt=3.4 minutes, m/z [M+H]⁺=457

Example 23 methyl(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate

Carbonyldiimidazole (0.324 g, 1.6 equiv.) was suspended in anhydrousdichloromethane (4 mL) and the suspension was left at room temperaturefor 15 minutes.(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide(0.800 g) was then added with stirring and the resultant solution wasleft at room temperature for 16 hours. The mixture was then treated withmethanol (10 mL) and left at room temperature overnight. The solventswere removed under reduced pressure and the residue was purified bypreparative plate chromatography on silica (20×20 cm plates×4 elutedwith 1:3 ethyl acetate:cyclohexane×5) to give: methyl(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate(0.453 g, 66%)

HPLC Rt=3.42 minutes, m/z [M+H]⁺=471

Similarly prepared:

Example 24propyl(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate

HPLC Rt=3.71 minutes, m/z [M+H]⁺=499

Example 25 1-(acetyloxy)ethyl(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate

(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoicacid (example 22) (0.130 g) was stirred in anhydrous DMF (1 mL) andanhydrous potassium carbonate (0.020 g, 0.5 eq.) was added. The mixturewas stirred at room temperature for 1 hour then cooled to −10° C.(ice-salt bath). The heterogeneous mixture was treated with 1-bromoethylacetate (0.120 mL, excess) and stirred for 3.5 hours keeping the bathtemperature between −10 and −5° C. It was then partitioned between DCMand 1M HCl aq. (20 mL each). The organic phase was separated(hydrophobic frit) and evaporated under reduced pressure to give apurple gum; this was purified by SPE cartridge (5 g, silica eluted with(i) cyclohexane×2, (ii) DCM×2, (iii) diethyl ether×2, (iv) ethylacetate×2, (v) methanol×2 to give 1-(acetyloxy)ethyl(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate(0.081 g) as a yellow foam.

HPLC Rt=3.5 minutes, m/z [M+H]⁺=543

Similarly prepared:

In the table below, Examples 26, 54-55, 66-104, 107-117, 124-131 wereprepared via method 1. The t-butyl ester Example 39 was prepared viaperchloric acid-catalysed transesterification of the corresponding acid(Example 22) with t-butyl acetate by the procedure of T Kolasa and M JMiller; Journal of Organic Chemistry (1990), 55(6), 1711-21. OtherExamples in the table below were prepared via method 5.

Eg Rt/ +ve −ve No. Regno Mwt min ion ion name Eg 26

511.6 3.6 512 510 (2R)-N-(tert-butyl)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3- (2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1- yl]ethanamide 27

537.5 3.4 538 536 (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2,2,2- trifluoroethyl)ethanamide 28

543.6 3.2 544 542 (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2,2- dimethoxyethyl)ethanamide 29

513.6 3.3 513 511 (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2- methoxyethyl)ethanamide 30

527.6 3.4 528 none (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2- methoxyethyl)-N- methylethanamide 31

571.7 3.3 572 none (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-bis(2- methoxyethyl)ethanamide 32

528.6 2.7 529 none (2R)-2-(2,4-difluorophenyl)-N-[2-(dimethylamino)ethyl]-2- [(2R,5R)-2-isobutyl-3,6-dioxo-5-(2-phenylethyl)piperazin-1- yl]-N-methylethanamide 33

654.7 2.7 541 539 (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-[2- (dimethylamino)ethyl]-N- methylethanamidetrifluoroacetate 34

511.6 3.6 512 none (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N- isopropyl-N-methylethanamide 35

471.6 3.2 472 470 (2R)-2-(2,4-difluorophenyl)-2-[(2R,5R)-2-isobutyl-3,6-dioxo- 5-(2-phenylethyl)piperazin-1-yl]-N,N-dimethylethanamide 36

497.6 3.5 498 none (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-4-methyl-2,5-dioxopiperazin-1-yl]-N,N- dimethylethanamide 37

554.7 2.7 555 none (2R)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-4-[2- (dimethylamino)ethyl]-6-isobutyl-2,5-dioxopiperazin-1- yl}-N,N-dimethylethanamide 38

527.6 3.3 528 526 [{(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1- yl]ethanoyl}(methyl)amino]acetic acid 39

512.6 3.7 513 511 tert-butyl(2R)-(2,4- difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-1- yl]ethanoate 40

583.7 3.6 584 none tert-butyl [{(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3- (2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1- yl]ethanoyl}(methyl)amino] acetate 41

525.6 3.3 526 524 (3R,6R)-1-[(1R)-1-(2,4- difluorophenyl)-2-(3-methoxyazetidin-1-yl)-2- oxoethyl]-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutylpiperazine-2,5-dione 42

509.6 3.5 510 none (3R,6R)-1-[(1R)-1-(2,4- difluorophenyl)-2-oxo-2-pyrrolidin-1-ylethyl]-3-(2,3- dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione 43

561.1 2.7 525 none (3R,6R)-1-[(1R)-1-(2,4- difluorophenyl)-2-oxo-2-piperazin-1-ylethyl]-3-(2,3- dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione hydrochloride 43a

652.7 2.7 539 583 (M + 45) (3R,6R)-1-[(1R)-1-(2,4- difluorophenyl)-2-(4-methylpiperazin-1-yl)-2- oxoethyl]-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutylpiperazine-2,5-dione trifluoroacetate 44

602.7 3.3 603 601 (3R,6R)-1-{(1R)-1-(2,4- difluorophenyl)-2-[4-(methylsulfonyl)piperazin-1-yl]- 2-oxoethyl}-3-(2,3-dihydro-1H-inden-2-yl)-6- isobutylpiperazine-2,5-dione 45

525.6 3.2 526 524 (3R,6R)-1-[(1R)-1-(2,4- difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro- 1H-inden-2-yl)-6-[(1S)-1-methylpropyl]piperazine-2,5- dione 46

525.6 3.2 526 524 (3R,6R)-1-[(1R)-1-(2,4- difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro- 1H-inden-2-yl)-6-[(1R)-1-methylpropyl]piperazine-2,5- dione 47

541.7 3.6 542 540 (3R,6R)-1-[(1R)-1-(2,4- difluorophenyl)-2-oxo-2-thiomorpholin-4-ylethyl]-3-(2,3- dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione 48

573.7 3.3 574 572 (3R,6R)-1-[(1R)-1-(2,4- difluorophenyl)-2-(1,1-dioxidothiomorpholin-4-yl)-2- oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6- isobutylpiperazine-2,5-dione 49

557.7 3.1 558 556 (3R,6R)-1-[(1R)-1-(2,4- difluorophenyl)-2-(1-oxidothiomorpholin-4-yl)-2- oxoethyl]-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutylpiperazine-2,5-dione 50

560.6 3 561 none (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methyl- N-(pyridin-4- ylmethyl)ethanamide 51

605.7 3.5 606 604 (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(3,4- dimethoxybenzyl)ethanamide 52

605.7 3.5 606 604 (2S)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(3,4- dimethoxybenzyl)ethanamide 53

538.6 3.4 539 537 (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(1,3- thiazol-2-yl)ethanamide 54

511.6 3.6 512 510 (2R)-N-(tert-butyl)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3- (2,3-dihydro-1H-inden-2-yl)-6-[(1R)-1-methylpropyl]-2,5- dioxopiperazin-1-yl}ethanamide 55

511.6 3.6 512 510 (2R)-N-(tert-butyl)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3- (2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5- dioxopiperazin-1-yl}ethanamide 56

437.5 3.3 438 436 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(4-fluorophenyl)ethanamide 57

481.6 3 482 480 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2- hydroxyethyl)ethanamide 58

509.6 3.4 510 508 [[(2R)-2-[(3R,6R)-3-(2,3- dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1- yl]-2-(4-flourophenyl)ethanoyl](methyl)amino] acetic acid 59

509.6 3.4 510 508 methyl{[(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl) ethanoyl]amino}acetate 60

564.7 2.6 565 563 (3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-1-{(1R)-1-(4-fluorophenyl)-2-[4-(2- methoxyethyl)piperazin-1-yl]-2-oxoethyl}-6-isobutylpiperazine- 2,5-dione 61

534.7 2.6 535 533 (3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-1-[(1R)-1-(4-fluorophenyl)-2-(4-methyl-1,4- diazepan-1-yl)-2-oxoethyl]-6-isobutylpiperazine-2,5-dione 62

548.7 2.6 549 547 (3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-1-[(1R)-2-[4-(dimethylamino)piperidin-1-yl]- 1-(4-fluorophenyl)-2-oxoethyl]-6-isobutylpiperazine-2,5-dione 63

550.7 2.7 551 549 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2-morpholin- 4-ylethyl)ethanamide 64

548.7 2.8 549 547 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2-piperidin-1- ylethyl)ethanamide 65

619.7 3.9 620 618 (2R)-N-[2-(benzyloxy)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4- fluorophenyl)ethanamide

Similarly prepared:

Eg Rt/ +ve −ve No. Regno Mwt min ion ion name 66

529.6 3.8 530 528 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]- N-isopropyl-2-[4-(trifluoromethyl)phenyl]ethanamide 67

475.6 3.6 476 474 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-(4-methylphenyl)ethanamide 68

510.1 3.8 510 508 (2R)-N-(tert-butyl)-2-(4-chlorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-1-yl]ethanamide 69

505.7 3.5 506 504 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(4-methoxyphenyl)ethanamide 70

559.7 3.8 560 558 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-[4-(trifluoromethoxy)phenyl]ethanamide 71

490.6 3.4 491 489 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]- N-isopropyl-2-[4-(methylamino)phenyl]ethanamide 72

504.7 3.6 505 503 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(dimethylamino)phenyl]-N- isopropylethanamide 73

530.7 3.7 553 (M + Na) 529 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-(4-pyrrolidin-1- ylphenyl)ethanamide 74

532.7 3.7 533 531 (2R)-2-[4-(diethylamino)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N- isopropylethanamide 75

504.6 3.1 505 503 4-[(1R)-1-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin- 1-yl]-2-(isopropylamino)-2-oxoethyl]benzamide 76

518.6 3.0 519 517 (2R)-2-[4-(acetylamino)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N- isopropylethanamide 77

532.7 3.2 533 531 (2R)-2-[3-(acetylamino)phenyl]-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin- 1-yl]ethanamide 78

539.7 3.3 540 538 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]- N-isopropyl-2-[4-(methylsulfonyl)phenyl]ethanamide 79

532.7 3.3 533 531 4-{(1R)-2-(tert-butylamino)-1-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-oxoethyl}-N- methylbenzamide 80

568.7 3.4 569 567 (2R)-N-(tert-butyl)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6- [(1R)-1-methylpropyl]-2,5-dioxopiperazin-1-yl}-2-{4- [(methylamino)sulfonyl]phenyl}ethanamide 81

533.7 3.6 532 534 methyl 4-{(1R)-2-(tert-butylamino)-1-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2- oxoethyl}benzoate 82

541.8 3.3 542 540 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(1H-pyrazol-1- yl)phenyl]ethanamide 83

542.8 3.3 543 541 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(1H-1,2,4- triazol-1-yl)phenyl]ethanamide 84

542.8 3.2 543 541 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(1H-1,2,3- triazol-1-yl)phenyl]ethanamide 85

541.7 3.5 542 540 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(1H-pyrazol-3- yl)phenyl]ethanamide 86

541.8 3.3 542 540 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(1H-pyrazol-3- yl)phenyl]ethanamide 87

519.4 3.4 520 518 3-{(1R)-2-(tert-butylamino)-1-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl- 2,5-dioxopiperazin-1-yl]-2-oxoethyl}phenylboronic acid 88

541.7 3.0 542 540 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(1H-imidazol- 2-yl)phenyl]ethanamide 89

541.7 3.1 542.0 540 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[3-(1H-imidazol- 1-yl)phenyl]ethanamide 90

541.7 3.0 542 540 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(1H-imidazol-1- yl)phenyl]ethanamide 91

560.8 3.4 561 559 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-morpholin-4- ylphenyl)ethanamide 92

541.7 3.3 542 540 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(1H-pyrazol- 4-yl)phenyl]ethanamide 93

599.8 3.9 600 598 (2R)-N-(tert-butyl)-2-[4-(2-tert-butyl-2H-tetraazol-5-yl)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]ethanamide 94

562.7 2.9 563 none (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-{4-[2-(dimethylamino)ethoxy]phenyl} ethanamide trifluoroacetate 95

560.8 3.0 561 559 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(4-hydroxypiperidin-1-yl)phenyl]-N- isopropylethanamide 96

616.9 3.5 617 none (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]ethanamide 97

573.8 2.9 574 none (2R)-N-(tert-buty1)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-[4-(4-methylpiperazin-1-yl)phenyl]ethanamide 98

654.0 4.1 654 652 (2R)-N-(tert-butyl)-2-[4-(3,5-ditert-butyl-1H-pyrazol-1-yl)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide 99

581.7 4.0 582 580 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4′-methoxy-1,1′- biphenyl-4-yl)ethanamide 100

569.8 3.9 none 568 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4′-fluoro-1,1′- biphenyl-4-yl)ethanamide 101

614.8 4.3 615 613 (2R)-N-(tert-butyl)-2-[4-(4-tert-butyl-1,3-thiazol-2-yl)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]ethanamide102

658.9 3.6 659 657 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-{4′-[(ethylamino)sulfonyl]-1,1′-biphenyl-4- yl}ethanamide 103

552.8 3.6 553 551 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-pyridin-2- ylphenyl)ethanamide 104

552.8 3.3 553 551 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-pyridin-3- ylphenyl)ethanamide 105

522.7 2.4 523 none (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-{4-[(dimethylamino)methyl]-2- fluorophenyl}-N,N-dimethylethanamide 106

495.6 2.9 496 none (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[2-fluoro-4-(hydroxymethyl)phenyl]- N,N-dimethylethanamide 107

3.4 498 496 (2R)-2-(2,5-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl- 2,5-dioxopiperazin-1-yl]-N-isopropylethanamide 108

3.6 512 510 (2R)-N-(tert-butyl)-2-(3,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1- yl]ethanamide 109

3.6 512 510 (2R)-N-(tert-butyl)-2-(3,5-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1- yl]ethanamide 110

3.6 512 510 (2R)-N-(tert-butyl)-2-(2,3-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1- yl]ethanamide 111

3.7 530 528 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(2,4,5-trifluorophenyl)ethanamide 112

3.7 530 528 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(2,3,4-trifluorophenyl)ethanamide 113

3.6 530 528 (2S)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(2,4,6-trifluorophenyl)ethanamide 114

3.8 526 524 (2R)-N-(tert-butyl)-2-(2,3-difluoro-4-methylphenyl)-2-[(3R,6R)-3-(2,3-dihydro- 1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl[ethanamide 115

3.8 528 526 (2R)-N-(tert-butyl)-2-(4-chloro-3-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro- 1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide 116

3.7 530 528 (2R)-2-(3,4-dichlorophenyl)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxopiperazin-1-yl}- N-isopropylethanamide 117

3.7 580 578 (2R)-2-[3-chloro-4- (trifluoromethoxy)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl- 2,5-dioxopiperazin-1-yl]-N-isopropylethanamide 118

3.0 482 480 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(3-fluoro-4-hydroxyphenyl)-N,N- dimethylethanamide 119

3.3 496 494 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isopropyl-2,5-dioxopiperazin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-N- isopropylethanamide 120

3.6 524 522 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(2-fluoro-4- methoxyphenyl)ethanamide 121

3.1 540 538 {4-[(1R)-1-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(dimethylamino)-2-oxoethyl]-2- fluorophenoxy}acetic acid 122

3.6 596 594 tert-butyl {4-[(1R)-1-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(dimethylamino-2-oxoethyl]-2-fluorophenoxy}acetate 123

3.3 553 none 4-[(1R)-1-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(dimethylamino)-2-oxoethyl]-2- fluorophenyl dimethylcarbamate124

3.5 none 552 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(2-fluoro-4,5- dimethoxyphenyl)ethanamide 125

3.7 524 522 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluoro-3- methoxyphenyl)ethanamide 126

3.8 none 570/ 572 (2R)-2-(4-bromo-2-fluorophenyl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin- 1-yl]ethanamide 127

3.5 523 521 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(dimethylamino)-3-fluorophenyl]-N- isopropylethanamide 128

3.7 540 538 (2R)-N-(tert-butyl)-2-(3-chloro-4-methoxyphenyl)-2-[(3R,6R)-3-(2,3- dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide 129

3.3 565 563 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(3-fluoro-4-morpholin-4-ylphenyl)-N- isopropylethanamide 130

3.2 579 577 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[2-fluoro-4-(4-hydroxypiperidin-1- yl)phenyl]-N-isopropylethanamide131

3.3 587 585 (2R)-N-(tert-butyl)-2-](3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-{2-fluoro-4- [(methylsulfonyl)amino]phenyl}ethanamide

Hydroxylated metabolites of(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamidewere prepared as follows:

2 litres of growing cell cultures of Streptomyces rimosus BS33 was usedto biotransform GW796679x. 500 mg of GW796679X was added after 3 daysgrowth and the broth harvested after another 5 days incubation. Atharvest, 2 litres of methanol was added, then the cells removed bycentrifugation. Methanol was removed from the supernatant byevaporation. The compounds were then extracted with ethyl acetate,evaporated to dryness, and purified by preparative HPLC to give examples132, 133, 134 and 135.

132

485.5 2.9 486 484 (2R)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-6-isobutyl-2,5-dioxopiperazin-1-yl}- N-methylethanamide 133

485.5 2.9 486 484 (2R)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3-[(2R)-1-hydroxy-2,3-dihydro-1H-inden-2-yl]-6-isobutyl-2,5-dioxopiperazin-1-yl}- N-methylethanamide 134

485.5 2.9 486 484 (2R)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3-[(2R)-1-hydroxy-2,3-dihydro-1H-inden-2-yl]-6-isobutyl-2,5-dioxopiperazin-1-yl}- N-methylethanamide 135

485.5 3.1 486 530 (M + 45) (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl- 2,5-dioxopiperazin-1-yl]-N-(hydroxymethyl)ethanamide

Example 136(2R)-2-(1-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isoaroplethanamide

Benzofuran-5-carboxaldehyde (215 mg, 1.47 mmol) and D-leucine t-butylester hydrochloride (329 mg, 1.47 mmol) were dissolved in methanol (1.5ml) and triethylamine (0.205 ml, 1.47 mmol) added. The mixture, a paleyellow solution, was left to stand at room temperature overnight (23.5hours). Then Boc-D-indanylglycine (429 mg, 1.47 mmol) was added followedby isopropylisonitrile (0.138 ml, 1.51 mmol). The mixture, a yellowsolution, was left to stand at room temperature overnight (23.5 hours)before the solvent was evaporated under reduced pressure to leave ayellow gum. The gum was dissolved in 4M hydrogen chloride in dioxan (3ml, 12 mmol) and left to stand at room temperature for 7.5 hours beforeit was evaporated under reduced pressure to leave an orange/brown gum.The gum was dissolved in methanol (2 ml) and 4M hydrogen chloride indioxan (1 ml, 4 mmol) added. The mixture was left to stand at roomtemperature for 5.5 hours before the solvent was removed by evaporationunder reduced pressure. The residue was dissolved in dichloromethane (4ml) and triethylamine (0.5 ml, excess) added. The mixture was stirred atroom temperature overnight (18.3 hours) before the solvent was removedby evaporation under reduced pressure. The residue was loaded indichloromethane onto a SPE column (10 g silica, Mega Bond Elutcartridge, pre-eluted with cyclohexane). The column was eluted stepwise(40-45 ml each step) with 100% chloroform, 3:1 cyclohexane:diethylether, 1:1 cyclohexane:diethyl ether, 1:3 cyclohexane:diethyl ether,100% diethyl ether, 1:1 cyclohexane:ethyl acetate, 1:2 cyclohexane:ethylacetate and 100% ethyl acetate. The 1:3 cyclohexane:diethyl ether to 1:2cyclohexane:ethyl acetate fractions inclusive were combined to give apale yellow solid (336 mg). The solid was loaded in dichloromethane onto6 preparative chromatography plates (silica gel 60 plates, 20×20 cm²).The plates were eluted four times with 30:1 dichloromethane:isopropanol.The required band was extracted with 9:1 ethyl acetate: methanol to give(2R)-2-(1-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamideas a white solid (141 mg, 0.28 mmol)

HPLC Rt=3.46 minutes; m/z [M+H]⁺=502.

¹H NMR δ 7.95 (d, 1H), 7.73 (d, 1H), 7.68 (d, 1H), 7.53 (d, 1H), 7.37(dd, 1H), 7.16 (m, 4H), 6.79 (d, 1H), 5.79 (d, 1H), 5.37 (s, 1H), 4.11(m, 1H), 4.03 (br dd, 1H), 3.99 (dd, 1H), 3.16-2.97 (m, 3H), 2.95-2.78(m, 2H), 1.79 (m, 1H), 1.69 (m, 1H), 1.33 (m, 1H), 1.09 (t, 6H), 0.78(d, 3H), 0.67 (d, 3H).

Similarly prepared

Example 137(2R)-2-(1,2,3-benzothiadiazol-6-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide

HPLC Rt=3.50 minutes; m/z [M+H]⁺=534.

¹H NMR δ 8.66 (d, 1H), 7.82 (d, 1H), 7.67 (dd, 1H), 7.20 (m, 4H), 6.72(br d, 1H), 6.13 (s, 11H), 5.19 (s, 11H), 4.06 (br dd, 11H), 4.00 (dd,11H), 3.18 (m, 11H), 3.07 (m, 2H), 2.92 (m, 1H), 2.81 (m, 1H), 1.86 (m,1H), 1.80 (m, 1H), 1.54 (m, 1H), 1.36 (s, 9H), 0.85 (d, 3H), 0.78 (d,3H).

Example 138(2R)-2-(2,3-dihydro-1-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide

HPLC Rt=3.34 minutes; m/z [M+H]⁺=504.

¹H NMR δ 7.81 (br s, 1H), 7.18 (m, 5H), 6.79 (d, 1H), 6.44 (br d, 1H),5.50 (d, 1H), 5.06 (s, 1H), 4.61 (t, 2H), 4.08 (m, 1H), 3.96 (m, 2H),3.22 (t, 2H), 3.15 (m, 1H), 3.07 (d, 2H), 2.90 (m, 1H), 2.79 (dd, 1H),1.82 (m, 1H), 1.71 (m, 1H), 1.42 (m, 1H), 1.12 (dd, 6H), 0.83 (d, 3H),0.77 (d, 3H).

Example 139(2R)-2-(1,3-benzodioxol-5-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide

HPLC Rt=3.48; m/z [M+H]⁺=520

¹H NMR (CDCl₃) δ 7.21 (m, 2H), 7.16 (m, 2H), 6.97 (d, 1H), 6.88 (dd,1H), 6.82 (d, 1H), 6.58 (m, 1H), 6.06 (m, 2H), 5.64 (s, 1H), 5.02 (m,1H), 3.95 (m, 2H), 3.16 (m, 1H), 3.07 (m, 2H), 2.89 (m, 1H), 2.77 (m,1H), 1.82 (m, 1H), 1.71 (m, 1H), 1.41 (m, 1H), 1.32 (s, 9H), 0.83 (d,3H), 0.79 (d, 3H)

Example 140(2R)-2-(benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

MethylN-[(1R)-2-{[2-(benzyloxy)phenyl]amino}-1-(benzofuran-5-yl)-2-oxoethyl]-L-leucinate

To a suspension of L-leucine (2.62 g) in methanol (250 ml) at −30° C.under nitrogen was added a solution of benzofuran-5-carbaldehyde (2.92g) in methanol (15 ml) and a suspension of 2-benzyloxyphenylisonitrile(4.19 g) in methanol (15 ml). The reaction was stirred at −30° C. for 2hours and then allowed to warm to room temperature and stirred for afurther 3 days. The solvent was removed in vacuo and the residue waspassed through a Biotage™ column (3×90 g) eluting with cyclohexane:ethylacetate (5:1) to afford after evaporation of the appropriate fractionsmethylN-[(1R)-2-{[2(benzyloxy)phenyl]amino}-1-(benzofuran-5-yl)-2-oxoethyl]-L-leucinate(5.11 g).

HPLC Rt=3.97 minutes, m/z [M+H]⁺=499

MethylN-{(1R)-1-(benzofuran-5-yl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate

A mixture of palladium on carbon (10%, 500 mg), methylN-[(1R)-2-{[2-(benzyloxy)phenyl]amino}-1-(benzofuran-5-yl)-2-oxoethyl]-L-leucinate(5.1 g) and ethyl acetate (60 ml) was stirred under a hydrogenatmosphere for 5 hours. The reaction was then filtered through Celiteand the filter pad was washed with further portions of ethyl acetate.The combined organic fractions were evaporated to give methylN-{(1R)-1-(benzofuran-5-yl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate(3.429 g).

HPLC Rt=3.49 min, m/z [M+H]⁺=411

Methyl N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate

A solution of methylN-{(1R)-1-(benzofuran-5-yl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate(410 mg) and 1,1′-thiocarbonyldiimidazole (196 mg) in dichloromethane (5ml) was left to stand for 18 hours. Water (20 □l) was added to thereaction mixture and this was then stirred rapidly for 30 minutes. Afterthis, 1H-Benzotriazolium, 1-[bis(dimethylamino)methylene]-,tetrafluoroborate(1-), 3-oxide (TBTU, 710 mg) and a solution ofdimethylamine in tetrahydrofuran (3 ml of 2M solution) were added. Thereaction mixture was stirred for a further 18 hours and was then passeddown an SPE (5 g, silica) eluting with a gradient (3:1 to 1:2cyclohexane:ethyl acetate). The required fractions were combined andevaporated to furnish methylN-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (140mg).

HPLC Rt=2.70 minutes m/z [M+H]⁺=347

N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucine

To a solution of methylN-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (520mg) in methanol (5 ml) was added a solution of lithium hydroxide (91 mg)in water (3 ml). After stirring vigorously for 24 hours the solvent wasremoved in vacuo. The residue was diluted with water (10 ml) thenneutralised with 2N hydrochloric acid. This solution was applied to anOasis™ cartridge (2×6 g) and eluted with water (×2) and methanol (×2).The required fractions were combined and evaporated to affordN-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (478 mg).

HPLC Rt=2.27 minutes m/z [M+H]⁺=333

(2R)-2-(benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

To a solution of(2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoicacid (419 mg) in dry tetrahydrofuran (5 ml) at −20° C. under a nitrogenatmosphere was added N-methylmorpholine (158 μl) and a solution ofisopropylchloroformate in toluene (1.0M, 1.44 ml). After 10 minutes, asolution ofN-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (478 mg)in dimethylformamide (5 ml) was added and the reaction was allowed towarm to room temperature. After 20 hours, the solvent was removed invacuo and the residue was dissolved in 4N hydrochloric acid in dioxan (4ml). After 4 hours methanol (13 ml) was added and the reaction was leftto stand for a further 18 hours. The solvent was then removed in vacuoand the residue was separated between dichloromethane and saturatedsodium bicarbonate solution. The organic phase was evaporated in vacuoand the residue was applied to an SPE (10 g, silica). The product waseluted using an ethyl acetate: methanol gradient (3:1 to 1:3) to afford(2R)-2-(benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide(51 mg).

HPLC Rt=3.36 minutes, m/z [N+H]⁺=488

¹H NMR (D₆-DMSO) δ 8.47 (d, 1H), 8.07 (d, 1H), 7.71 (m, 1H), 7.69 (d,1H), 7.38 (dd, 1H), 7.21 (m, 2H), 7.12 (m, 2H), 7.03 (m, 1H), 6.47 (s,1H), 3.88 (m, 1H), 3.69 (dd, 1H), 3.07-2.67 (m, 5H), 2.87 (s, 3H), 2.77(s, 3H), 1.40-1.70 (m, 2H), 0.46 (m, 1H), 0.42 (d, 3H), 0.02 (d, 3H)

Example 141(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-(2-methyl-1-benzofuran-5-yl)ethanamide

(2RS)-2-(2-methyl-1-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide

A mixture of 2-methyl-5-formylbenzofuran (1.26 g), (D)-leucine methylester hydrochloride (1.57 g), triethylamine (1.2 ml) and methanol (20ml) was stirred at room temperature for 6 hours and then left to standfor 19 hours. N-benzylcarbonyl-(D)-indanylglycine (2.80 g) and2-benzyloxy-phenylisocyanide (1.89 g) were then added sequentially andthe mixture stirred for 2 days. The reaction mixture was concentratedunder reduced pressure and diluted with ethyl acetate. This was washedwith 1N hydrochloric acid, saturated sodium bicarbonate solution andbrine. The organic phase was dried over MgSO₄ and concentrated in vacuo.The residue was diluted with ethyl acetate (100 ml) and acetic acid (10ml) and hydrogenated at atmospheric pressure over 10% palladium onactivated carbon (1.5 g). After 4 hours the catalyst was removed byfiltration through a pad of celite and washed withdichloromethane/methanol (500 ml of 1:1 v/v). The filtrate and washingswere combined, evaporated under reduced pressure. The residue wasseparated between ethyl acetate and water. The organic phase was washedwith water, saturated sodium bicarbonate solution and brine. The organicphase was dried over MgSO₄ and evaporated under reduced pressure. Theresidue was applied to a silica cartridge (100 g) and eluted withcyclohexane/ethyl acetate (500 ml of 3:1, 2:1, 1:1 v/v) and ethylacetate (500 ml). The required fractions were combined and evaporated invacuo to give(2RS)-2-(2-methylbenzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide(1.58 g).

HPLC Rt=3.60 minutes; m/z [M+H]⁺=566.

(2R)-2-(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl-N,N-dimethyl-2-(2-methyl-1-benzofuran-5-yl)ethanamide

Carbonyldiimidazole (92 mg, 1.6 equiv.) was suspended in anhydrousdichloromethane (5 mL) and the suspension was left at room temperaturefor 15 minutes.(2RS)-2-(2-methylbenzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide(200 mg) was then added and the mixture was stirred at room temperaturefor 5 hours. The resulting brown solution was then treated with a 2.0Msolution of dimethylamine in tetrahydrofuran (1.066 mL, 6 equiv.) andthe resulting mixture was stirred for 30 minutes and then left to standat room temperature for 18 hours. The reaction mixture was diluted withdichloromethane (2 mL) and washed with 1M hydrochloric acid (2 mL). Theorganic phase was separated using a hydrophobic frit and was evaporatedunder reduced pressure to leave a brown gum. The crude product wasapplied to a silica cartridge (10 g). This was eluted with cyclohexane(100 ml), cyclohexane/ethyl acetate (100 ml of 2:1, 3:2, 1:1, 2:3 and1:2 v/v), ethyl acetate (200 ml) and ethyl acetate/methanol (100 ml of19:1 v/v). The required fractions were combined and evaporated in vacuoto give(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-(2-methyl-1-benzofuran-5-yl)ethanamideas an off-white solid (88 mg).

HPLC Rt=3.40 minutes; m/z [M+H]⁺=502.

¹H NMR (CDCl₃) δ 7.52 (d, 1H), 7.43 (d, 1H), 7.27-7.13 (m, 5H), 6.54 (s,1H), 6.38 (m, 1H), 6.31 (d, 1H), 4.24 (m, 1H), 3.99 (dd, 1H), 3.22-3.05(m, 3H), 2.99 (s, 3H), 2.86 (m, 1H), 2.82 (s, 3H), 2.75 (m, 1H), 2.48(m, 3H), 1.45 (m, 1H), 1.36 (m, 1H), 0.57 (m, 1H), 0.51 (d, 3H), 0.19(d, 3H).

Similarly prepared:—

Example 142(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-(2-methyl-1-benzofuran-5-yl)ethanamide

HPLC Rt=3.40 minutes; m/z [M+H]⁺=516.

¹H NMR (CDCl₃) δ 7.57 (m, 1H), 7.41 (d, 1H), 7.28-7.11 (m, 5H), 6.61 (m,1H), 6.37 (m, 1H), 5.49 (d, 1H), 5.23 (s, 1H), 4.11 (m, 1H), 4.02-3.93(m, 2H), 3.19-3.05 (m, 3H), 2.92 (m, 1H), 2.77 (m, 1H), 2.48 (m, 3H),1.79 (m, 1H), 1.70 (m, 1H), 1.38 (m, 1H), 1.10 (m, 6H), 0.78 (d, 3H),0.69 (d, 3H).

Example 143(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-1-[(1R)-1-(2-methyl-1-benzofuran-5-yl)-2-morpholin-4-yl-2-oxoethyl]piperazin-2,5-dione

HPLC Rt=3.38 minutes; m/z [M+H]⁺=544.

¹H NMR (CDCl₃) δ 7.51 (d, 1H), 7.45 (d, 1H), 7.26-7.14 (m, 5H), 6.57 (s,1H), 6.39 (m, 1H), 6.34 (m, 1H), 4.20 (m, 1H), 3.99 (m, 1H), 3.73-3.33(6H), 3.22-3.03 (m, 5H), 2.88 (m, 1H), 2.75 (m, 1H), 2.49 (m, 3H), 1.45(m, 1H), 1.37 (m, 1H), 0.54 (m, 1H), 0.51 (d, 3H), 0.20 (d, 3H).

Example 144(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(2-fluoro-1-benzofuran-5-yl)-N,N-dimethylethanamide

HPLC Rt=3.39 minutes; m/z [M+H]⁺=505.

¹H NMR (CDCl₃) δ 7.56 (d, 1H), 7.45 (d, 1H), 7.32 (dd, 1H), 7.23 (m,2H), 7.16 (m, 2H), 6.55 (s, 1H), 6.23 (d, 1H), 5.89 (d, 1H), 4.22 (m,1H), 3.99 (dd, 1H), 3.21-3.04 (m, 3H), 3.00 (s, 3H), 2.87 (m, 1H), 2.84(s, 3H), 2.75 (m, 1H), 1.47 (m, 1H), 1.38 (m, 1H), 0.58-0.49 (m, 4H),0.22 (d, 3H).

5-Bromo-2-fluoro-1-benzofuran

5-Bromobenzofuran-2-carboxylic acid (4.68 g) was suspended in carbontetrachloride (150 ml) and water (50 ml). To this was added sodiumbicarbonate (3.36 g), followed by Selectflor (7.1 g) and the reactionmixture was stirred rapidly for 20 hours. The reaction mixture wasdiluted with dichloromethane and 2N sodium hydroxide solution. Theorganic phase was separated, washed with brine and dried over anhydrousMgSO₄. The solvent was evaporated under reduced pressure at roomtemperature. The residue was applied to a silica cartridge (20 g) andeluted with diethyl ether. This gave 5-bromo-2-fluoro-1-benzofuran (1.4g).

¹H NMR (CDCl₃) δ 7.61 (d, 1H), 7.36 (dd, 1H), 7.26 (d, 1H), 5.84 (dd,1H).

2-Fluoro-5-formyl-1-benzofuran

A slurry of magnesium powder (219 mg) and iodine (cat) in drytetrahydrofuran (3 ml) was heated at 50° C. under nitrogen for 20minutes. 5-Bromo-2-fluoro-1-benzofuran (1.4 g) was dissolved in drytetrahydrofuran (6 ml). A 1 ml portion of the solution was added to theslurry at 50° C. without stirring. After 30 minutes the rest of thesolution was added slowly and the reaction was heated at reflux for 3hours. The reaction was cooled in an ice/water bath anddimethylformamide (1 ml) was added dropwise maintaining the temperaturebelow 10° C. After 1 hour a mixture of 2N hydrochloric acid (12.5 ml)and brine (12.5 ml) was added. The reaction mixture was extracted usingethyl acetate (3×25 ml). The combined organics were washed with brineand dried over anhydrous magnesium sulphate. The solvent was removed invacuo and the residue applied to a silica cartridge (50 g). This waseluted with cyclohexane, cyclohexane/ethyl acetate (6:1, 5:1 v/v). Thisgave 2-fluoro-5-formyl-1-benzofuran (376 mg).

¹H NMR (CDCl₃) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.83 (dd, 1H), 7.54 (d,1H), 6.01 (dd, 1H).

Example 145(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(2-fluoro-1-benzofuran-5-yl)-N-isopropylethanamide

HPLC Rt=3.42 minutes; m/z [M+H]⁺=520.

¹H NMR (CDCl₃) δ 7.61 (d, 1H), 7.42 (d, 1H), 7.31 (dd, 1H), 7.21 (m,2H), 7.16 (m, 2H), 6.70 (d, 1H), 5.89 (d, 1H), 5.57 (d, 1H), 5.18 (s,1H), 4.11 (m, 1H), 3.98 (m, 2H), 3.16 (m, 1H), 3.08 (m, 2H), 2.91 (m,1H), 2.78 (m, 1H), 1.82 (m, 1H), 1.73 (m, 1H), 1.41 (m, 1H), 1.12 (d,3H), 1.10 (d, 3H), 0.81 (d, 3H), 0.72 (d, 3H).

Example 146(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2-fluoro-1-benzofuran-5-yl)-2-morpholin-4-yl-2-oxoethyl]-6-isobutylpiperazine-2,5-dione

HPLC Rt=3.35 minutes; m/z [M+H]⁺=548.

¹H NMR (CDCl₃) δ 7.55 (d, 1H), 7.47 (d, 1H), 7.31 (dd, 1H), 7.27-7.14(m, 4H), 6.58 (s, 1H), 6.38 (d, 1H), 5.91 (d, 1H), 4.19 (m, 1H), 4.00(dd, 1H), 3.73-3.50 (m, 5H), 3.39 (m, 1H), 3.23-3.04 (m, 5H), 2.87 (m,1H), 2.76 (m, 1H), 1.47 (m, 1H), 1.40 (m, 1H), 0.53 (d, 3H), 0.51 (m,1H), 0.24 (d, 3H).

Example 147(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(1H-indol-6-yl)-N,N-dimethylethanamide

HPLC Rt=3.38 minutes; m/z [M+H]⁺=487.

¹H NMR (CDCl₃) δ 9.03 (s, 1H), 7.66 (d, 1H), 7.49 (d, 1H), 7.30 (m, 1H),7.21 (m, 1H), 7.18-7.10 (m, 4H), 7.02 (m, 1H), 6.57 (s, 1H), 6.55 (m,1H), 4.29 (m, 1H), 4.00 (dd, 1H), 3.22-3.03 (m, 3H), 3.00 (s, 3H),2.92-2.73 (m, 5H), 1.40 (m, 1H), 1.33 (m, 1H), 0.57 (m, 1H), 0.45 (d,3H), 0.06 (d, 3H).

Example 148(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(1H-indol-6-yl)-N-methyl-N-[2-(methylsulphonyl)ethyl]ethanamide

HPLC Rt=3.20 minutes; m/z [M+H]⁺=579.

¹H NMR (CDCl₃) δ 9.62 (s, 1H), 7.64 (d, 1H), 7.41 (d, 1H), 7.30 (m, 1H),7.26-7.10 (m, 6H), 6.51 (m, 1H), 6.48 (s, 1H), 4.18 (m, 1H), 4.05-3.90(m, 2H), 3.68-3.50 (m, 2H), 3.28-3.01 (m, 4H), 2.96-2.69 (m, 8H), 1.41(m, 2H), 0.65 (m, 1H), 0.47 (d, 3H), −0.10 (d, 3H).

Example 149(2R)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

(2RS)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-benzyloxyphenyl)ethanamide

A mixture of 5-formylbenzothiophene (2.0 g), (D)-leucine methyl esterhydrochloride (2.24 g), triethylamine (1.72 ml) and methanol (20 ml) wasstirred at room temperature for 24 hours.N-tert-butoxycarbonyl-(D)-indanylglycine (3.59 g) and2-benzyloxy-phenylisocyanide (2.58 g) were then added sequentially andthe mixture stirred for 4 days. Then the solvent was removed underreduced pressure. The residue was taken up in dichloromethane (20 ml)and 4M hydrogen chloride in 1,4-dioxane (20 ml) and the mixture wasstirred at room temperature for 2 hours. The solvent and hydrogenchloride were evaporated under reduced pressure. The crude material wasdissolved in dichloromethane (30 ml) and triethylamine (10 ml) added.The mixture was stirred for 18 hours before the dichloromethane andexcess of triethylamine were removed under reduced pressure. The crudeproduct was dissolved in dichloromethane (100 ml) and washed with 1Nhydrochloric acid (2×100 ml) and brine. The organic phase was dried overMgSO₄ and evaporated in vacuo to yield(2RS)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-benzyloxyphenyl)ethanamideas a brown foam (7.5 g).

HPLC Rt=3.88 minutes, m/z [M+H]⁺=658.

(2RS)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide

(2RS)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-benzyloxyphenyl)ethanamide(1.0 g) was dissolved in dichloromethane (5 ml) and to this was addeddropwise a 1.0M solution of BBr₃ in dichloromethane (2.0 ml). Thereaction mixture was stirred at room temperature for 2 hours. To thereaction mixture was added 1N hydrochloric acid (30 ml) anddichloromethane (20 ml). The phases were separated and the organic phasewas washed with 1N hydrochloric acid (30 ml) and brine (30 ml). Theorganic phase was dried over MgSO₄ and evaporated in vacuo. The residuewas purified by Biotage™ flash column chromatography, eluting with 3:2ethyl acetate:cyclohexane. The required fractions were combined andevaporated in vacuo to give(2RS)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide(210 mg).

HPLC Rt=3.55 minutes, m/z [M+H]⁺=568.

(2R)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

Carbonyldiimidazole (100 mg) was suspended in anhydrous dichloromethane(1 mL) and the suspension was left at room temperature for 15 minutes.2RS)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide(200 mg) was then added and the mixture was stirred at room temperaturefor 5 hours 20 minutes. The resulting brown solution was then treatedwith a 2.0M solution of dimethylamine in tetrahydrofuran (1.0 mL, 6equiv.) and the resulting mixture was stirred for 30 minutes and thenleft to stand at room temperature for 18 hours 15 minutes. The reactionmixture was evaporated under reduced pressure. The crude product waspurified by silica column chromatography eluting with 1:1 v/v ethylacetate:cyclohexane. The required fractions were combined and evaporatedin vacuo to give(2R)-2-(benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamideas a white solid (90 mg).

HPLC Rt=3.35 minutes, m/z [M+H]⁺=504.

¹H NMR (CDCl₃) δ 7.94 (d, 1H), 7.89 (m, 1H), 7.70 (d, 1H), 7.54 (d, 1H),7.41 (m, 1H), 7.35 (d, 1H), 7.23 (m, 1H), 7.13 (m, 3H), 6.63 (s, 1H),4.25 (m, 1H), 4.02 (dd, 1H), 3.23-3.04 (m, 3H), 3.01 (s, 3H), 2.93-2.77(m, 5H), 1.50-1.32 (m, 2H), 0.52 (m, 1H), 0.49 (d, 3H), 0.12 (d, 3H).

Compounds 150-169 and 174-175 were prepared via method 1. Compound 170was prepared via method 2. Compounds 171, 172 and 173 were prepared viamethod 5.

Rt/ MH MH No. Regno MWt min + − Name 150

517.7 3.62 518 516 (2R)-N-(tert-butyl)-2-(2,3-dihydro-1-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobulyl-2,5- dioxopiperazin-1-yl]ethanamide151

516.6 3.12 517 515 2-(1H-1,2,3-benzotriazol-5-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin- 1-yl]acetamide 152

533.7 3.42 534 (2R)-N-(tert-butyl)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]ethanamide153

555.6 3.71 556 554 (2R)-N-(tert-butyl)-2-(2,2-difluoro-1,3-benzodioxol-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]ethanamide154

532.7 3.32 533 531 (2R)-2-(1,3-benzothiazol-6-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide 155

530.7 3.18 531 529 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(1-methyl-1H- 1,2,3-benzotriazol-5-yl)ethanamide156

530.7 3.22 531 529 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(1-methyl-1H- 1,2,3-benzotriazol-6-yl)ethanamide157

629.7 3.06 514 (2R)-2-(1H-benzimidazol-5-yl)-N-(tert-butyl)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1R)-1-methyipropyl]-nl2,5-dioxopiperazin-1-yl}ethanamide trifluoroacetate 158

515.7 3.72 516 514 (2R)-2-(1-benzofuran-2-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl])-6-isobutyl-2,5-nldioxopiperazin-1-yl]ethanamide 159

530.7 3.3 531 529 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(2-methyl-1,3- benzoxazol-5-yl)ethanamide 160

530.7 3.35 531 529 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(2-methyl-1,3- benzoxazol-6-yl)ethanamide 161

519.7 3.37 520 518 (2R)-2-(1,2,3-benzothiadiazol-6-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]- N-isopropylethanamide 162

514.7 3.41 515 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-isopropyl-2-(1-methyl-1H-indol-5-yl)ethanamide 163

529.6 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-(2- oxo-2H-chromen-6-yl)ethanamide164

517.7 3.53 518 516 (2R)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide 165

501.6 3.42 502 500 (2R)-2-(1-benzofuran-6-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide 166

500.6 3.35 501 499 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1 -yl]-2-(1H-indol-6-yl)-N-isopropylethanamide 167

515.7 4.88 516 514 2R-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1- yl]-N-isopropyl-2-(1-methyl-1H-benzimidazol-2-yl)acetamide 168

515.7 4.32 516 514 (2R)-2-(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-isopropyl-2-(1-methyl-1H-benzimidazol-6- yl)ethanamide 169

515.7 2.65 516 514 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-isopropyl-2-(1-methyl-1H-benzimidazol-5- yl)ethanamide 170

502.6 3.35 503 501 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N,N-dimethyl-2-(3-methyl-1,2-benzisoxazol-5- yl)ethanamide 171

486.6 3.07 487 485 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(1H-indol-5-yl)-N,N-dimethylethanamide 172

487.6 2.94 488 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(1H-indazol-5-yl)-N,N-dimethylethanamide 173

487.6 2.99 488 486 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(1H-indazol-6-yl)-N,N-dimethylethanamide 174

511.7 3.56 512 (2R,S)-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-isopropyl-2-(2-naphthyl)acetamide 175

512.7 3.19 513 (2R,S)-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-isopropyl-2-quinolin-6-ylacetamide

Example 176(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide

To a solution of 5-trifluoromethyl-furan-2-carbaldehyde (140mg)[prepared as in ref. Chem. Heterocycl. Compd. 13, 1977, 1280-1282 byR. V. Grigorash, V. V. Lyalin, L. A. Alekseeva and L. M. Yagupol'skii:5-Trifluoromethylfuran Derivatives] in methanol (1.1 ml) was addedtriethylamine (118 μl) and (D)-leucine t-butyl ester hydrochloride (190mg). The mixture was left to stand for 16.33 hours before(2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoicacid (246 mg) and isopropylisocyanide (77.4 μl) were sequentially added.The mixture, a yellow solution, was left to stand for 24 hours beforethe solvent was removed in vacuo. The residue was dissolved in 4Mhydrogen chloride in dioxane (3 ml) and left to stand for 6.75 hours atambient temperature. After this time, the solvent was removed in vacuo.The residue was dissolved in methanol (4 ml) and treated with a solutionof 4M hydrogen chloride in dioxane (0.2 ml) and was left to standovernight. After this time, the solvent was removed in vacuo. Theresidue was stirred in dioxane (9.5 ml) containing triethylamine (0.5ml) and dichloromethane (5 ml) for 4.75 hours. Then the mixture wasevaporated in vacuo to leave a light brown solid. This crude materialwas purified by SPE column (10 g, silica Mega Bond Elut™) elutingstepwise with 100% chloroform, 4:1 cyclohexane:diethyl ether, 3:1cyclohexane:diethyl ether, 2:1 cyclohexane:diethyl ether, 1:1cyclohexane:diethyl ether, 1:2 cyclohexane:diethyl ether, 1:3cyclohexane:diethyl ether, 100% diethyl ether, 1:1 ethylacetate:cyclohexane, 2:1 ethyl acetate:cyclohexane, 3:1 ethylacetate:cyclohexane, 100% ethyl acetate. The 1:2 cyclohexane:diethylether to 2:1 ethyl acetate:cyclohexane fractions inclusive were combinedto give an orange gum (215 mg). The gum was purified further, toseparate the isomers, by preparative plate chromatography. Whatman PK6Fsilicagel 60 plates 20×20 cm², eluted in 1:1 ethyl acetate:cyclohexanesix times and extracted with 9:1 ethyl acetate:methanol to give(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide(64 mg),

HPLC Rt=3.59 minutes; m/z [M+H]⁺=520.

¹H NMR (CDCl₃) δ 7.88 (d, 1H), 7.16 (m, 4H), 6.85 (d, 1H), 6.74 (d, 1H),6.30 (d, 1H), 5.73 (s, H), 4.19 (dd, 1H), 4.08 (m, 1H), 3.97 (dd, 1H),3.14 (m, 2H), 3.01 (m, 1H), 2.84 (m, 2H), 1.81 (m, 1H), 1.68 (m, 1H),1.15 (d, 6H), 1.11 (m, 1H), 0.82 (dd, 6H).

Similarly prepared

Example 177(2S)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-(5-methylthien-2-yl)ethanamide

By the procedure of Example 176 but using5-methyl-thiophene-2-carbaldehyde

HPLC Rt=3.46 minutes; m/z [M+H]⁺=482.

¹H NMR (CDCl₃) δ 7.21 (m, 2H), 7.16 (m, 2H), 6.94 (d, 1H), 6.67 (d, 1H),6.63 (d, 1H), 5.73 (d, 1H), 4.94 (s, 1H), 4.07 (m, 1H), 3.93 (m, 2H),3.16 (dd, 1H), 3.05 (m, 2H), 2.93 (m, 1H), 2.77 (m, 1H), 2.47 (s, 3H),1.96 (m, 1H), 1.86 (m, 1H), 1.72 (m, 1H), 1.17 (d, 3H), 1.12 (d, 3H),0.94 (d, 3H), 0.92 (d, 3H)

Example 178(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide

N-[2-(benzyloxy)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[5-(trifluoromethyl)-2-furyl]acetamide

A mixture of 5-trifluoromethyl-furan-2-carbaldehyde (351 mg),(D)-leucine methyl ester hydrochloride (389 mg), triethylamine (0.298ml) and methanol (2.2 ml) was stirred at room temperature for 4 hoursand then left to stand for 19 hours.N-tert-butoxycarbonyl-(D)-indanylglycine (623 mg) and2-benzyloxy-phenylisocyanide (448 mg) were then added sequentially andthe mixture stirred for 7 hours before being left to stand at roomtemperature for 41 hours. Then the solvent was removed under reducedpressure to leave an orange/brown syrup. This was taken up in 4Mhydrogen chloride in 1,4-dioxane (2.8 ml) and the mixture was stirred atroom temperature for 2 hours. The solvent and hydrogen chloride wereevaporated under reduced pressure. The crude material was dissolved inmethanol (5 ml) and triethylamine (0.54 ml) added. The mixture wasstirred for 18 hours before the methanol and excess of triethylaminewere removed under reduced pressure. The crude product was purified byBiotage™ flash column chromatography (40 g silica cartridge eluted with1:5 ethyl acetate:cyclohexane (600 ml), 1:3 ethyl acetate:cyclohexane(400 ml) and 1:2 ethyl acetate:cyclohexane (450 ml)) to yieldN-[2-(benzyloxy)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[5-(trifluoromethyl)-2-furyl]acetamideas an orange solid (472 mg).

HPLC Rt=4.04 minutes, m/z [M+H]⁺=660.

2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)-2-[5-(trifluoromethyl)-2-furyl]acetamide

N-[2-(benzyloxy)phenyl]-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[5-(trifluoromethyl)-2-furyl]acetamide(469 mg) was dissolved in ethyl acetate (10 ml) and hydrogenated atatmospheric pressure over 10% palladium on activated carbon (100 mg).After 4 hours the catalyst was removed by filtration through glass fibrefilters and washed with ethyl acetate. The filtrate and washings werecombined, evaporated under reduced pressure and dried in vacuo at roomtemperature to leave a yellow/brown solid (400 mg). The solid was driedover P₂O₅ overnight to give2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)-2-[5-(trifluoromethyl)-2-furyl]acetamide(365 mg).

HPLC Rt=3.64 minutes, m/z [M+H]⁺=570.

(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide

Carbonyldiimidazole (78 mg, 1.6 equiv.) was suspended in anhydrousdichloromethane (1 mL) and the suspension was left at room temperaturefor 15 minutes.(R)—N-(2-Hydroxy-phenyl)-2-((3R,6R)-3-indan-2-yl-6-isobutyl-2,5-dioxo-piperazin-1-yl)-2-(5-trifluoromethyl-furan-2-yl)-acetamide(172 mg) was then added and the mixture was stirred at room temperaturefor 5 hours 20 minutes. The resulting brown solution was then treatedwith a 2.0M solution of dimethylamine in tetrahydrofuran (0.9 mL, 6equiv.) and the resulting mixture was stirred for 30 minutes and thenleft to stand at room temperature for 18 hours 15 minutes. The reactionmixture was diluted with dichloromethane (2 mL) and washed with 1Mhydrochloric acid (2 mL). The organic phase was separated using ahydrophobic frit and was evaporated under reduced pressure to leave abrown gum. The crude product was applied to 3 preparative chromatographyplates, which were eluted with 1:1 v/v ethyl acetate:cyclohexane. Therequired band was extracted with ethyl acetate to give the(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-[5-(trifluoromethyl)-2-furyl]ethanamideas a pale yellow solid (87 mg).

HPLC Rt=3.51 minutes, m/z [M+H]⁺=506.

¹H NMR (CDCl₃) δ 7.19 (m, 5H), 6.86 (dd, 1H), 6.64 (d, 1H), 6.61 (s,1H), 4.25 (m, 1H), 3.97 (dd, 1H), 3.20-3.02 (m, 3H), 3.01 (s, 3H), 2.96(s, 3H), 2.88 (m, 1H), 2.80 (m, 1H), 1.70 (m, 1H), 1.67 (m, 1H), 0.74(d, 3H), 0.70 (m, 1H), 0.63 (d, 3H).

Example 179(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-(2-methyl-1,3-oxazol-4-yl)ethanamide

By the procedure of Example 178, using(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)-2-(2-methyl-1,3-oxazol-4-yl)ethanamide

HPLC: Rt=2.88 minutes; m/z (M+H)⁺=453

(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)-2-(2-methyl-1,3-oxazol-4-yl)ethanamide

A mixture of 2-methyl-oxazole-4-carbaldehyde(1) (340 mg), (D)-leucinemethyl ester hydrochloride (568 mg), triethylamine (0.435 ml) andanhydrous methanol (20 ml) was stirred at room temperature for 18 hours.N-benzyloxycarbonyl-(D)-indanylglycine (1.015 g) and2-benzyloxy-phenylisocyanide (648 mg) were then added sequentially andthe mixture stirred for 12 days before being left to stand at roomtemperature for 10 days. The solvent was removed under reduced pressureto leave a dark orange gum which was dissolved in ethyl acetate (150 mL)and washed with 2M hydrochloric acid (100 mL), saturated sodiumbicarbonate solution (100 mL) and saturated sodium chloride solution (50mL) then dried over anhydrous magnesium sulphate and concentrated underreduced pressure to a volume of 5 mL. This crude solution was dilutedwith ethanol (80 mL) containing acetic acid (1.6 mL) and added undervacuum to 10% palladium on carbon (50% water, 425 mg). The resultingsuspension was stirred under an atmosphere of hydrogen for 20 hours,filtered (celite filteraid) washed with ethanol (50 mL) and the filtrateadded under vacuum to a second quantity of 10% palladium on carbon (50%water, 670 mg). The suspension was stirred under an atmosphere ofhydrogen for 2 hours, the hydrogenation apparatus was then evacuated andrefilled with hydrogen and the suspension stirred for a further 20hours. The suspension was filtered (celite filteraid) washed withethanol (200 mL) and the combined filtrates concentrated under reducedpressure. The residue was partitioned between saturated sodiumbicarbonate solution (100 mL) and dichloromethane (60 mL), then theorganic layer dried (hydrophobic frit) and the solvent removed underreduced pressure. Purification by Biotage flash chromatography (40 gsilica) eluting with ethyl acetate:cyclohexane (3:1, 300 mL) ethylacetate (300 mL) then ethyl acetate:methanol (20:1, 600 mL) gave(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)-2-(2-methyl-1,3-oxazol-4-yl)ethanamideas a brown foam (197 mg).

HPLC: Rt=3.28 minutes; m/z (M+H)⁺=517

Ref (1) CAS 113732-84-6

Example 180(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione

By the procedure of Example 179, using morpholine

HPLC: Rt=2.89 minutes; m/z (M+H)⁺=495

Example 181(2S)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-(5-methylthien-2-yl)ethanamide

By the procedure of Example 180, using 5-methyl-thiophene-2-carbaldehyde

HPLC Rt=3.25 minutes; m/z M⁺=468.

Example 182(2S)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(3-fluoro-5-methylthien-2-yl)-N,N-dimethylethanamide

By the procedure of Example 178, using3-fluoro-5-methyl-thiophene-2-carbaldehyde

HPLC: Rt=3.20 minutes; m/z M⁺=486

(3-Bromo-5-methyl-thiophen-2-yl)-[1,3]dioxane

3-Bromo-5-methyl-2-thiophenecarbaldehyde (1.00 g) was dissolved in dry1,4-dioxane (8 ml). Molecular sieves (4 Angstrom, 2 g), 1,3-propandiol(9 ml), p-toluene sulphonic acid (362 mg) were added and the mixture wasstirred under a nitrogen atmosphere, at room temperature, over night.Molecular sieves were removed by filtration and the filtrate evaporated.The residue was taken up with ethyl acetate and washed with saturatedsolution of sodium carbonate. The aqueous was extracted with more ethylacetate and the combined layers washed with brine, dried over magnesiumsulphate, filtrated and concentrated to a yellow oil (1 g).

Purification was performed by filtration on a SPE cartridge (Silica-10g) using dichloromethane as eluent. The solution was eventuallyconcentrated to yield 2-(3-bromo-5-methyl-thiophen-2-yl)-[1,3]dioxane asa yellow solid (1.18 g).

¹H-NMR (CDCl₃, 400 MHz): 6.60 ppm (s, 1H); 5.72 ppm (s, 1H); 4.23 ppm(m, 2H); 3.98 ppm (m, 2H); 2.44 ppm (d, 3H); 2.22 ppm (m, 1H); 1.42 ppm(m, 1H).

3-Fluoro-5-methyl-thiophene-2-carbaldehyde

To a solution of 2-(3-bromo-5-methyl-thiophen-2-yl)-[1,3]dioxane (1.16g) in dry tetrahydrofuran (10 ml), under a nitrogen atmosphere, at −78°C., 1.6M n-butyl lithium in hexane (3.30 ml) was added dropwise. After15 minutes stirring, N-fluoro-benzene-sulfonyl-imide (1.66 g) was addedportionwise. The solution was stirred at −78° C. for further 10 minutes,allowed to warm to room temperature and then stirred for a further 60minutes. The reaction was quenched with water (5 ml), diluted withdiethyl ether (20 ml) and washed with 1N sodium hydroxide (30 ml). Theaqueous was extracted with diethyl ether again (2×10 ml), the combinedorganic layers were dried over magnesium sulphate, filtrated andevaporated. The residue was redissolved in 1,4-dioxane (15 ml) and water(10), p-toluene sulphonic acid (837 mg) was added and the solution wasstirrer at room temperature, over night. Neutralised with a saturatedsolution of sodium bicarbonate (10 ml), then extracted with ether twice.The organic was dried over magnesium sulphate and evaporated at reducedpressure (200 mbar). The residual dioxane was removed by distillation atreduced pressure, the residue further purified by flash chromatography(petroleum ether/dichloromethane 55/45), giving3-fluoro-5-methyl-thiophene-2-carbaldehyde as a colourless oil (366 mg),approximately 70% pure.

¹H-NMR (CDCl₃, 400 MHz): δ 9.93 ppm (s, 1H); 6.62 ppm (s, 1H); 2.52 ppm(m, 3H).

Similarly prepared:

Compounds 183-206, 213, 215, 218, 222-225 were prepared via method 1.Compounds 207, 208, 216, were prepared via method 2. Compounds 209-212,214, 217, 219-221 and 226 were prepared via method 5.

Eg Rt/ +ve −ve No. Structure MWt min ion ion name 183

467.7 3.4 468 466 (2S)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-isopropyl-2-thien-2-ylethanamide 184

546.6 3.6 546/ 548 546/ 544 (2S)-2-(5-bromothien-2-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N- isopropylethanamide 185

546.6 3.6 546/ 548 544/ 546 (2S)-2-(4-bromothien-2-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N- isopropylethanamide 186

502.1 3.6 501- 3 499- 501 (2S)-2-(5-chlorothien-2-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N- isopropylethanamide 187

467.7 3.3 468 466 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-isopropyl-2-thien-3- ylethanamide 188

544.8 3.4 545 543 (2S)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-isopropyl-2-(5-pyridin-2- ylthien-2-yl)ethanamide 189

451.6 3.3 452 450 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(2-furyl)-N-isopropylethanamide 190

465.7 3.4 466 464 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)- 6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(3-furyl)ethanamide 200

508.7 2.9 509 507 5-[1-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(isopropylamino)-2-oxoethyl]-N-methyl-3-furamide 201

508.7 3 509 507 5-[(1R)-1-[(3R,6R)-3-(2,3- dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1- yl]-2-(isopropylamino)-2-oxoethyl]-N-methyl-2-furamide 202

530.5 3.5 529/ 531 527/ 529 (2R)-2-(5-bromo-2-furyl)-2-[(3R,6R)-3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N- isopropylethanamide 203

479.7 3.5 480 478 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(4,5-dimethyl-2-furyl)-N- isopropylethanamide 204

465.7 3.4 466 464 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-isopropyl-2-(5-methyl-2- furyl)ethanamide 205

477.6 3.3 478 476 (2R)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)- 6-isobutyl-2,5-dioxopiperazin-1-yl]-2-pyrimidin-5-ylethanamide 206

465.7 2.9 466 464 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-isopropyl-2-(1-methyl-1H- pyrazol-4-yl)ethanamide 207

468.7 3 469 none (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N,N-dimethyl-2-(2-methyl-1,3- thiazol-4-yl)ethanamide 208

522.6 3.4 523 521 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N,N-dimethyl-2-[2-(trifluoromethyl)- 1,3-thiazol-4-yl]ethanamide 209

462.7 3.1 463 none (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N,N-dimethyl-2-(6-methylpyridin-3- yl)ethanamide 210

558.7 3.3 559 557 (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-1-{(1R)- 2-morpholin-4-yl-2-oxo-1-[6-(trifluoromethyl)pyridin-3- yl]ethyl}piperazine-2,5-dione 211

464.6 2.7 465 463 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N,N-dimethyl-2-(6-oxo-1,6- dihydropyridin-3-yl)ethanamide 212

478.6 3.04 479.23 477.26 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(6-methoxypyridin-3-yl)-N,N- dimethylethanamide 213

479.6 3.03 480 478 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(1,3-dimethyl-1H-pyrazol-5-yl)-N- isopropylethanamide 214

466.56 3.1 467 — (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-2-(2-ethyl-1,3-oxazol-4-yl)-N,N- dimethylethanamide 215

482.6 3.58 483 481 N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6- isobutyl-2,5-dioxopiperazin-1-yl]-2-(1,3-thiazol-2-yl)acetamide 216

522.6 3.46 523 521 2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N,N-dimethyl-2-[2-(trifluoromethyl)- 1,3-thiazol-5-yl]acetamide 217

478.6 3.07 479 477 (2R)-2-(2-cyclopropyl-1,3-oxazol-4-yl)-2-[(3R,6R)-3-(2,3- dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1- yl]-N,N-dimethylethanamide 218

520.5 3.47 521 519 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-isopropyl-2-[2-(trifluoromethyl)- 1,3-oxazol-4-yl]ethanamide 219

554.7 2.8 555 553 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-methyl-2-(6-methylpyridin-3-yl)-N-[2- (methylsulfonyl)ethyl]ethanamide 220

604.7 2.7 605 603 (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-1-{(1R)- 2-[4-(2-methoxyethyl)piperazin-1-yl]-2-oxo-1-[5- (trifluoromethyl)-2- furyl]ethyl}piperazine-2,5-dione221

585.6 2.8 586 584 (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5- dioxopiperazin-1-yl]-N-methyl-N-[(1-methyl-1H-imidazol-2- yl)methyl]-2-[5- (trifluoromethyl)-2-furyl]ethanamide 222

462.6 3.29 463 461 2-((3R,6R)-3-Indan-2-yl-6-isobutyl-2,5-dioxo-piperazin-1- yl)-N-isopropyl-2-pyridin-2-yl-acetamide 223

462.6 3.09 463 461 2-((3R,6R)-3-Indan-2-yl-6-isobutyl-2,5-dioxo-piperazin-1- yl)-N-isopropyl-2-pyridin-3-yl-acetamide 224

516.7 3.41 517 515 N-Cyclohexyl-2-((3R,6R)-3-indan-2-yl-6-isobutyl-2,5-dioxo- piperazin-1-yl)-2-(6-methyl-pyridin-2-yl)-acetamide 225

462.6 2.93 463 461 2-((3R,6R)-3-Indan-2-yl-6-isobutyl-2,5-dioxo-piperazin-1- yl)-N-isopropyl-2-pyridin-4-yl-acetamide 226

466.6 3.06 467 — (R)-2-(2,5-Dimethyl-oxazol-4-yl)-2-((3R,6R)-3-indan-2-yl-6- isobutyl-2,5-dioxo-piperazin-1-yl)-N,N-dimethylacetamide

Example 227(3R,6R)-1-[(1R)-1-(2,4-Difluorophenyl)-2-(3-fluoroazetidin-1-yl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione

The azetidinol (Example 15) (57 mg) in anhydrous dichloromethane (2 mL)was stirred at −5° C. and diethylaminosulfur trifluoride (50 μL, excess)was added in one portion. The mixture was left at room temperatureovernight and saturated aqueous sodium hydrogen carbonate (3 mL) wasadded. The mixture was diluted with dichloromethane (10 mL) and theorganic phase was separated using a hydrophobic frit and blown down withnitrogen. The crude reaction mixture was purified using themass-directed autoprep system to give(3R,6R)-1-(1R)-[1-(2,4-difluorophenyl)-2-(3-fluoroazetidin-1-yl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione(26 mg) as a white solid.

HPLC Rt=3.34 minutes, m/z [M+H]⁺=514

PHARMACY EXAMPLES Tablets

a)

Compound of the invention 50.0 mg Lactose 70.0 mg MicrocrystallineCellulose 70.0 mg Cross-linked polyvinylpyrrolidone 8.0 mg MagnesiumStearate 2.0 mg Compression weight 200.0 mg

The compound of the invention, microcrystalline cellulose, lactose andcross-linked polyvinylpyrrolidone are sieved through a 500 micron sieveand blended in a suitable mixer. The magnesium stearate is sievedthrough a 250 micron sieve and blended with the active blend. The blendis compressed into tablets using suitable punches.

b)

Compound of the invention 50.0 mg Lactose 120.0 mg Pregelatinised Starch20.0 mg Cross-linked polyvinylpyrrolidone 8.0 mg Magnesium Stearate 2.0mg Compression weight 200.0 mg

The compound of the invention, lactose and pregelatinised starch areblended together and granulated with water. The wet mass is dried andmilled. The magnesium stearate and cross-linked polyvinylpyrrolidone arescreened through a 250 micron sieve and blended with the granule. Theresultant blend is compressed using suitable tablet punches.

Capsules

a)

Compound of the invention 50.0 mg Lactose 148.0 mg Magnesium Stearate2.0 mg Fill weight 200.0 mg

The compound of the invention and pregelatinised starch are screenedthrough a 500 micron mesh sieve, blended together and lubricated withmagnesium stearate, (meshed through a 250 micron sieve). The blend isfilled into hard gelatine capsules of a suitable size.

b)

Compound of the invention 50.0 mg Lactose 132.0 mg Polyvinylpyrrolidone8.0 mg Cross-linked polyvinylpyrrolidone 8.0 mg Magnesium Stearate 2.0mg Fill weight 200.0 mg

The compound of the invention and lactose are blended together andgranulated with a solution of polyvinylpyrrolidone. The wet mass isdried and milled. The magnesium stearate and cross-linkedpolyvinylpyrrolidone are screened through a 250 micron sieve and blendedwith the granules. The resultant blend is filled into hard gelatinecapsules of a suitable size.

Injection Formulation

% w/v Compound of the invention 0.10 Water for injections B.P. to 100.00

Sodium chloride may be added to adjust the tonicity of the solution andthe pH may be adjusted to that of maximum stability and/or to facilitatesolution of the compound of the invention using dilute acid or alkali orby the addition of suitable buffer salts. Solubilisers, such ascosolvents, may also be added to facilitate solution of the compound ofthe invention. Antioxidants and metal chelating salts may also beincluded. The solution is clarified, made up to final volume with waterand the pH remeasured and adjusted if necessary, to provide 1 mg/ml ofthe compound of formula (I).

The solution may be packaged for injection, for example by filling andsealing in ampoules, vials or syringes. The ampoules, vials or syringesmay be aseptically filled (e.g. the solution may be sterilised byfiltration and filled into sterile ampoules under aseptic conditions)and/or terminally sterilised (e.g. by heating in an autoclave using oneof the acceptable cycles). The solution may be packed under an inertatmosphere of nitrogen.

Preferably the solution is filled into ampoules, sealed by fusion of theglass and terminally sterilised.

Further sterile formulations are prepared in a similar manner containing0.05, 0.20 and 0.5% w/v of the compound of the invention, so as toprovide respectively 0.5, 2 and 5 mg/ml of the compound of theinvention.

Measurement of Oxytocin Antagonist A

Assay Buffer used throughout the assay: 50 mM HEPES, 10 mM MgCl2, 0.125mg/ml BSA, pH adjusted to 7.4 with KOH.

hOT-CHO membranes were prepared at a concentration of 0.3 mg protein/mlin assay buffer. Test compounds were initially dissolved in DMSO (to 10mM) and diluted in DMSO (Beckman Biomek FX). 1 μl of compound wastransferred to black 384 assay plates (NUNC) using a Biomek FX. 20 μl of1 nM Bodipy TMR Oxytocin (Perkin Elmer) in assay buffer was added to allwells (Labsystems Multidrop) then 20 μl membrane added to all wells(Multidrop). Plates were incubated at room temp for 60 min.

Polarisation was read on LJL Analyst (λEx=535 nm, λm=580 nM,λDichroic=555 nm). Data were fitted to a 4 parameter logistic equation.An estimated Ki was calculated as IC50/5.

In the above test compounds of the invention in general have a pKi valuewithin the range of 7 to 11. Thus the compounds of examples 1 to 227have a pKi within the range 8.5 to 10.8.

The compounds of the invention are essentially non toxic attherapeutically active doses. Thus compound of the example 10 has beenadministered to rats at doses of up to 300 mg/kg p.o for 4 days. and noadverse toxicological effects were observed.

1. A method of treating a disease selected from pre-term labour,dysmenorrhea, and endometriosis comprising administering to a human inneed thereof an effective amount of a pharmaceutical compositioncomprising a compound of the following formula

or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers; wherein R₁ is a 2-indanyl group;R₂ represents C₃₋₆cycloalkyl, C₁₋₆alkyl optionally substituted by aC₁₋₂alkoxy, a C₁₋₂alkylthio, a di-C₁₋₂alkyl-amino or a C₃₋₆ cycloalkylgroup, or a 5 or 6 membered heterocyclic group containing a singlehetero atom selected from O, S or N, which nitrogen atom carries ahydrogen atom or a methyl or ethyl group; R₃ represents an optionallysubstituted phenyl, a 5 membered heteroaryl group which is unsubstitutedor substituted by one or more groups selected from halogen,trifluoromethyl, C₁₋₄alkyl, cycloalkyl, heteroaryl, saturatedheterocyclic, or phenyl, a 6 membered heteroaryl group which isunsubstituted or substituted by 1 to 3 C₁₋₄alkyl, or trifluoromethyl, oralkoxy groups, or a fused bicyclic ring system containing 9-10 ringmembers which ring system contains a benzene and which ring membersinclude 0 to 3 heteroatoms selected from O, S or N; R₄ represents OH,OC₁₋₄ alkyl optionally substituted with C₁₋₄alkylcarbonyloxy, or NR₅R₆;where, R₅ represents hydrogen, C₁₋₆alkyl optionally substituted withC₁₋₄alkoxy, or C₃₋₇cycloalkyl, R₆ represents hydrogen, methyl,C₁₋₄alkoxy, C₃₋₇cycloalkyl, C₂₋₄alkyl optionally substituted with one ormore R₅₀, or C₂₋₄alkyl optionally substituted with one or more R₅₅, orR₆ represents a phenyl or benzyl group optionally substituted by one ormore methoxy or benzyloxy groups, an optionally substitutedheteroarylmethyl group, a heteroaryl group, C₃₋₇ cycloalkyl, or thegroup CH₂CONR₉R₁₀, or R₅ and R₆ together with the nitrogen to which theyare attached form a 3 to 7 membered saturated heterocycle optionallysubstituted with one or more R₆₀ which heterocycle optionally containsan additional heteroatom selected from oxygen, sulphur and nitrogen,wherein the sulphur atom may be in an oxidised form and the additionalnitrogen atom either carries a hydrogen atom or a C₁₋₄alkyl or aC₁₋₄alkanoyl group or a C₁₋₄alkylsulphonyl group or a C₁₋₃ alkoxyC₂₋₄alkyl, where, R₅₀ is selected from the group consisting of: carboxyl,C₁₋₄alkylsulphonyl, or C₁₋₄alkoxycarbonyl, and R₅₅ is selected from thegroup consisting of: halogen, hydroxy, C₁₋₄alkoxy, or NR₇R₈, where, R₇and R₈ independently represent hydrogen or C₁₋₄alkyl or together form a3 to 7 membered saturated heterocyclic ring which optionally contains anadditional heteroatom selected from O, S or N and which heterocyclicgroup may be substituted by 1 to 3 groups selected from C₁₋₃alkyl,hydroxy, C₁₋₃ alkoxy optionally substituted by C₃₋₆ cycloalkyl oroptionally substituted phenyl, C₃₋₆cycloalkyl or NR_(c)R_(d), whereinR_(c) and R_(d) each independently represent a group selected fromC₁₋₃alkyl optionally substituted by C₃₋₆ cycloalkyl or optionallysubstituted phenyl, or C₃₋₆ cycloalkyl, R₉ represents hydrogen orC₁₋₄alkyl, and R₁₀ represents hydrogen, C₁₋₄alkyl optionally substitutedby a 5 or 6 membered heteroaryl group, or R₉ and R₁₀ together form a 5or 6 membered saturated heterocyclic ring and wherein the 6 memberedheterocyclic group optionally contains an additional heteroatom selectedfrom oxygen, sulphur or nitrogen and the additional nitrogen atom eithercarries a hydrogen atom or a C₁₋₄alkyl or C₁₋₄alkanoyl group, and R₆₀ isselected from the group consisting of: halogen, C₁₋₃alkyl, hydroxy, oxo,C₃₋₆cycloalkyl or NR_(e)R_(f) wherein R_(e) and R_(f) each independentlyrepresent a group selected from C₁₋₃alkyl optionally substituted by C₃₋₆cycloalkyl or optionally substituted phenyl or C₃₋₆ cycloalkyl.
 2. Amethod according to claim 1, wherein R₄ is hydroxy or the group NR₅R₆.3. A method according to claim 2, wherein the compound has thestereochemistry as defined in formula (1a)

wherein the groups R₁, R₂, R₃ and R₄ have the meanings defined in claim2.
 4. A method according to claim 3, wherein R₂ is a group selected from1-methylpropyl or 2-methylpropyl.
 5. A method according to claim 3,wherein R₃ is an optionally substituted phenyl group.
 6. A methodaccording to claim 3, wherein R₃ is a 5 membered heteroaryl group whichis unsubstituted or substituted by one or more groups selected fromhalogen, trifluoromethyl, C1-4 alkyl, cycloalkyl, heteroaryl, saturatedheterocyclic, or phenyl, or a 6 membered heteroaryl group which isunsubstituted or substituted by 1 to 3 C1-4 alkyl groups, ortrifluoromethyl, or alkoxy groups.
 7. A method according to claim 3,wherein R₃ is a fused bicyclic ring system containing 9-10 ring memberswhich is unsubstituted or substituted by a carbocyclic group or by up tothree hetero atoms selected from O, S or N and one of the fused rings isbenzene.
 8. A method according to claim 3, wherein R₃ is selected fromthe group consisting of: phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl,4-bromophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl,2,4-difluorophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl,2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2fluoro-4-bromophenyl, 4-chloro-3-fluorophenyl 2,3,4-trifluorophenyl2,4,5-trifluorophenyl or 2,4,6-trifluorophenyl,2-fluoro-4,5-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl,4-fluoro-3-methoxyphenyl, 2-fluoro-4 methoxyphenyl, 2-fluoro-4hydroxyphenyl, 2-fluoro-4-dimethylaminomethylphenyl,2-fluoro-4-hydroxymethylphenyl, 3-fluoro-4-(4-morpholino)phenyl,3-fluoro-4-carboxymethyloxyphenyl,3-fluoro-4-t-butyloxycarbonylmethyloxyphenyl,3-fluoro-4-dimethylaminocarbonyloxyphenyl, 3-chloro-4trifluoromethoxyphenyl, 2,3-difluoro-4-methyl-phenyl,4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl,4-methoxyphenyl, 4-methoxycarbonylphenyl, 3-methoxycarbonyphenyl,4-methylsulphonylphenyl, 4-methylaminocarbonylphenyl,4-aminocarbonylphenyl, 4-methylaminosulphonylphenyl,3-(3-pyrazyolyl)phenyl, 4-(3-pyrazolyl)phenyl, 4-(4-pyrazolyl)phenyl,4-(3-pyridyl)phenyl, 4-(2-pyridylphenyl), 4-(2-imidazolyl)phenyl,3-(2-imidazolyl)phenyl, 4-(1-t-butyl-tetrazol-5-yl)phenyl,4-methylaminophenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl,4-acetylaminophenyl, 3-acetylaminophenyl, 4-hydroxy-3-acetylaminophenyl,4-methylsulphonylaminophenyl, 4-N-methylpiperazinophenyl,4-N-pyrrolidinophenyl, 2-fluoro-4-(4-morpholino)phenyl,4-(4-morpholino)phenyl, 4-(4-hydroxypiperidino)phenyl,2-fluoro-4-(4-hydroxypiperidino)phenyl, 3-(1-pyrazolyl)phenyl,4-(1-pyrazolyl)phenyl, 4-(1-3,5 di-t-butylpyrazolyl)phenyl,3-(1-imidazolyl)phenyl, 4-(1-imidazolyl)phenyl,4-(1-1,2,4-triazolyl)phenyl, 4-(1-1,2,3-triazolyl)phenyl,4-(2-4,-t-butylthiazolyl)phenyl, 4-(5-2-t-butyltetrazolyl)phenyl, 4-(4spiro-1,3-dioxolanyl)piperidinophenyl, 4-(4-fluorophenyl)phenyl,4-(4-ethylaminosulphonylphenyl)phenyl, 4-dimethylaminoethoxyphenyl,3-(dihydroxyboryl)phenyl, 2-furanyl, 3-thienyl, 3-furanyl, 2-thienyl,4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-chloro-2-thienyl,3-fluoro-5-methyl-2-thienyl, 5-methyl-2-thienyl, 5-methyl-2-furanyl,5-bromo-2-furanyl, 4,5-dimethyl-2-furanyl, 5-trifluoromethyl-2-furanyl,2-furanyl-4-carboxylic acid methylamide, 2-furanyl-5-carboxylic acidmethylamide, 2-pyridyl, 6-methyl-2-pyridyl, 6-methyl-3-pyridyl,6-methoxy-3-pyridyl, 6-hydroxy-3-pyridyl, 6-trifluoromethyl-3-pyridyl,3-pyridyl, 4-pyridyl, 3,5-pyrimidinyl, 2-thiazolyl, 2-methyl-4-oxazolyl,2-ethyl-4-oxazolyl, 2-cyclopropyl-4-oxazolyl,2-trifluoromethyl-4-oxazolyl, 2,5-dimethyl-4-oxazolyl, 4-thiazolyl,2-methyl-4-thiazolyl, 2-trifluoromethyl-4-thiazolyl,2-trifluoromethyl-5-thiazolyl, 1-methyl-4-pyrazolyl,1,3-dimethyl-5-pyrazolyl, 5-(2-pyridyl)-2-thienyl,2,3-dihydro-1-benzofuran-5-yl, 1,3-benzodioxol-5-yl,1H-1,2,3-benzotriazol-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl,2,2-difluoro-1,3-benzodioxol-5-yl, 1,3-benzothiazol-6-yl,1-methyl-1H-1,2,3-benzotriazol-5-yl,1-methyl-1H-1,2,3-benzotriazol-6-yl, 1,2,3-benzothiadiazol-6-yl,2-methyl-1,3-benzoxazol-5-yl, 2-methyl-1,3-benzoxazol-6-yl,1-benzofuran-5-yl, 1-methyl-1H-lindol-5-yl, 1-benzothien-5-yl,1-benzofuran-6-yl, 1H-indol-6-yl, 1-methyl-1H-benzimidazol-6-yl,1-methyl-1H-benzimidazol-5-yl, 3-methyl-1,2-benzoisoxazol-5-yl,2-fluoro-1-benzofuran-5-yl, 1H-indol-5-yl, 2-methyl-1H-benzofuran-5-yl,1H-indazol-5-yl, 1H-indazol-6-yl, 1-benzofuran-2-yl and1-methyl-1H-benzimidazol-2-yl.
 9. A method according to claim 3, whereinR₅ is selected from the group consisting of hydrogen, C₁₋₄alkyl andC₁₋₄alkoxyC₂₋₄-alkyl; and R₆ is selected from the group consisting ofhydrogen, C₁₋₄alkoxy, C₁₋₄alkyl, C₁₋₄ alkyl substituted by 1 to 3halogen atoms, C₁₋₄alkyl substituted by alkoxycarbonyl or carboxyl,alkyl substituted by alkoxy, alkyl substituted by hydroxy, alkylsubstituted by dialkylamino, 2-benzyloxyphenyl, dimethoxybenzyl,optionally substituted heteroarylmethyl, heteroaryl, alkyl substitutedby NR₇R₈ wherein NR₇R₈ form a 6-membered heterocyclic ring andcycloalkyl; or NR₅R₆ represents, azetidino, 3-hydroxyazetidino,3-methoxyazetidino, pyrrolidino, piperidino, 4-dimethylaminopiperidino,4-methyl 1,4-diazepan-1-yl, morpholino, an optionally substitutedpiperazino ring, thiomorpholino or a sulphoxide or sulphone thereof. 10.A method according to claim 3, wherein the compound is selected from thegroup consisting of:(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide;(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide;(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-morpholinamide;(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide;(2R)—N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-[4-(4-hydroxypiperidin-1-yl)phenyl]ethanamide;(2R)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1R)-1-methylpropyl]-2,5-dioxopiperazin-1-yl}-2-(2-fluoro-4-morpholin-4-ylphenyl)-N-isopropylethanamide;(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide;(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide;(2R)—N-cyclopropyl-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide;(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methylethanamide;(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide;(3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione;(3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione;(3R,6R)-1-[(1R)-2-azetidin-1-yl-1-(2,4-difluorophenyl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione;(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyethyl)-N-methylethanamide;(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methyl-N-[2-(methylsulfonyl)ethyl]ethanamide;(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)ethanamide;(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methyl-N-(pyridin-2-ylmethyl)ethanamide;(3R,6R)-1-{(1R)-1-(2,4-difluorophenyl)-2-[4-(methylsulfonyl)piperazin-1-yl]-2-oxoethyl}-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione;(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-methoxy-N-methylethanamide;(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoicacid; methyl(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate;propyl(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate;1-(acetyloxy)ethyl(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate;(2R)—N-(tert-butyl)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1R)-1-methylpropyl]-2,5-dioxopiperazin-1-yl}ethanamide;(2R)—N-(tert-butyl)-2-(2,4-difluorophenyl)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxopiperazin-1-yl}ethanamide;(3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]piperazine-2,5-dione;(3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-morpholin-4-yl-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1R)-1-methylpropyl]piperazine-2,5-dione;(3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-(3-fluoroazetidin-1-yl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiperazine-2,5-dione;(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide;(2S)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-(5-methylthien-2-yl)ethanamide;(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-[5-(trifluoromethyl)-2-furyl]ethanamide;(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-(2-methyl-1,3-oxazol-4-yl)ethanamide;(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione;(2S)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-(5-methylthien-2-yl)ethanamide;(2S)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(3-fluoro-5-methylthien-2-yl)-N,N-dimethylethanamide;(2R)-2-(1-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide;(2R)-2-(1,2,3-benzothiadiazol-6-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide;(2R)-2-(2,3-dihydro-1-benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide;(2R)-2-(1,3-benzodioxol-5-yl)-N-(tert-butyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanamide;(2R)-2-(benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide;(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethyl-2-(2-methyl-1-benzofuran-5-yl)ethanamide;(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropyl-2-(2-methyl-1-benzofuran-5-yl)ethanamide;(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-1-[(1R)-1-(2-methyl-1-benzofuran-5-yl)-2-morpholin-4-yl-2-oxoethyl]piperazin-2,5-dione;(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(2-fluoro-1-benzofuran-5-yl)-N,N-dimethylethanamide;(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(2-fluoro-1-benzofuran-5-yl)-N-isopropylethanamide;(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2-fluoro-1-benzofuran-5-yl)-2-morpholin-4-yl-2-oxoethyl]-6-isobutylpiperazine-2,5-dione;(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(1H-indol-6-yl)-N,N-dimethylethanamide;and(2R)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide;or a pharmaceutically acceptable salt thereof.
 11. A method according toclaim 1 wherein the disease is pre-term labour.